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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Short-course Radiotherapy Versus Chemoradiotherapy, Followed by Consolidation Chemotherapy, and Selective Organ Preservation for MRI-defined Intermediate and High-risk Rectal Cancer Patients

Conditions
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Rectal Cancer Stage III

Intervention / Treatment
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* Drug: Oxaliplatin, 85 mg/m2
* Drug: 5FU; 2400 mg/m2
* Drug: 5FU, 250 mg/m2
* Drug: 5FU, 2400 mg/m2
* Drug: Oxaliplatin 50 mg/m2
* Drug: Folinic Acid, 400 mg/m2
* Radiation: Radiotherapy control, 5x5 Gy: 25 Gy
* Drug: Capecitabine, 1000 mg/m2
* Drug: Oxaliplatin 85 mg/m2
* Radiation: radiotherapy experimental, 30 x 1,8 Gy: 54 Gy
* Drug: Capecitabine, 825 mg/m2
* Drug: Oxaliplatin, 130 mg/m2


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Investigator-driven
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control arm<br>In the control arm patients receive 5x5 Gy followed by 9 cycles of consolidation chemotherapy mFOLFOX6 or alternatively 6 cycles of CAPOX, followed by re-staging at week 22-24 as established as new preferred neoadjuvant regimen by the RAPIDO trial. | Drug: Oxaliplatin, 85 mg/m2<br>* 85 mg/m2,2h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapy<br>* Other names: Control arm;Drug: 5FU; 2400 mg/m2<br>* 2400 mg/m2, 46h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, 134 of therapy for Control arm<br>* Other names: 5-FU, control arm;Drug: Folinic Acid, 400 mg/m2<br>* 2h-civ day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapyfor Control arm; 400 mg/m2, 2h-civ d 64, d78, d92, d106, d120, d134 of therapy for experimental arm<br>* Other names: Folinic Acid;Radiation: Radiotherapy control, 5x5 Gy: 25 Gy<br>* Control arm: 5x5 Gy (total: 25 Gy) 5 fractions<br>Drug: Capecitabine, 1000 mg/m2<br>* 1000 mg/m2 (twice daily) day1-14 every three weeks instead of 5FU optional<br>* Other names: Capecitabine;Drug: Oxaliplatin, 130 mg/m2<br>* day1every three weeks (optional)<br>* Other names: Oxaliplatin;|
| Experimental: Experimental arm<br>The experimental arm starts with Fluoropyrimidin/Oxaliplatin-based CRT (1.8 Gy to 45 Gy to the primary tumor and pelvic lymph nodes; followed by sequential boost of 9 Gy to the gross tumor volume) followed by consolidation chemotherapy with 6 cycles mFOLFOX6 or alternatively 4 cycles CAPOX, followed by re-staging at week 22-24. In both arms, for patients achieving a clinical complete response (cCR), as strictly assessed by clinical investigation, endoscopy and MRI, a W&W option with close follow-up is scheduled. In case of non-complete response, immediate TME surgery is performed. | Drug: 5FU, 250 mg/m2<br>* 250 mg/m2 per day, civ, on day 1-14, day 22-35 of radiotherapy;<br>* Other names: Experimental arm: 5-FU;Drug: 5FU, 2400 mg/m2<br>* 2400 mg/m2,46h-civ, d64, d78, d92, d106, d120, d134 of therapy<br>* Other names: experimental arm;Drug: Oxaliplatin 50 mg/m2<br>* 50 mg/m2, 2h-civ, d1, d8, d21, d29 of radiotherapy and<br>* Other names: Experimental arm;Drug: Folinic Acid, 400 mg/m2<br>* 2h-civ day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapyfor Control arm; 400 mg/m2, 2h-civ d 64, d78, d92, d106, d120, d134 of therapy for experimental arm<br>* Other names: Folinic Acid;Drug: Capecitabine, 1000 mg/m2<br>* 1000 mg/m2 (twice daily) day1-14 every three weeks instead of 5FU optional<br>* Other names: Capecitabine;Drug: Oxaliplatin 85 mg/m2<br>* 85 mg/m2, 2h-civ, d64, d78, d92, d106, d120, d134 of therapy<br>* Other names: experimental arm;Radiation: radiotherapy experimental, 30 x 1,8 Gy: 54 Gy<br>* 30 x 1.8 Gy (total: 54 Gy), 5 fractions per week<br>Drug: Capecitabine, 825 mg/m2<br>* 825 mg/m2 bid, per os, on day 1-14, 22-35 of RT instead of 5FU optional<br>* Other names: Capecitabine;Drug: Oxaliplatin, 130 mg/m2<br>* day1every three weeks (optional)<br>* Other names: Oxaliplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| organ preservation | it 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. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival | Disease-free survival | 3 years | 
| Rate of clinical complete response after TNT: | TNT total neoadjuvant therapy | 3 years | 
| Rate of immediate TME after TNT | TNT total neoadjuvant therapy TME total mesorectal excision | 3 years | 
| Cumulative incidence of locoregional regrowth after cCR | cCR clinical complete response | 3 years | 
| Rate of salvage surgery (LE/TME with or APR/stoma) after locoregional regrowth APR/stoma) after locoregional regrowth | LE local Exision; TME: Transanale endoscopic Mikrochirurgie; APR Abdomino perineal Rectum exstirpation | 3 years | 
| Cumulative incidence of local recurrence after (salvage) surgery surgery | Cumulative incidence of local recurrence after (salvage) surgery | 3 years | 
| Postoperative complications of (salvage) surgery | Postoperative complications of (salvage) surgery | 3 years | 
| Rate of sphincter-sparing (salvage) surgery | Rate of sphincter-sparing (salvage) surgery | 3 years | 
| Pathological TNM-staging | Pathological tumor evaluations;TNM tumor staging | 3 years | 
| R0 resection rate; negative circumferential resection rate | R0 Removal of the tumor in healthy tissue | 3 years | 
| Tumor regression grading according to Dworak | pathological response from scale 1-4 poor to very good ascending | 3 years | 
| Neoadjuvant rectal score | Neoadjuvant rectal score from low to high values means good to poor | 3 years | 
| Quality of TME according to MERCURY | Tumor response using MRI scale 1-5 from good to poor descending | 3 years | 
| Acute and late toxicity assessment according to NCI CTCAE V.5.0) CTCAE V.5.0) | CTCAE V.5.0 | 3 Yeears | 
| Quality of life C30 based on treatment arm and surgical procedures/organ preservation | Quality of life based on EORTC-QLQs-C30 | 3 years | 
| functional outcome based on treatment arm and surgical procedures/organ preservation | functional outcome based on Wexner score | 3 years | 
| Quality of life CR29 based on treatment arm and surgical procedures/organ preservation | Quality of life based on EORTC-QLQs-CR29 | 3 years | 
| Quality of life CPIN 20 based on treatment arm and surgical procedures/organ preservation | Quality of life based on EORTC-QLQs-CPIN20 Quality of life based on EORTC-QLQs-CPIN20 | 3 years | 
| Cumulative incidence of distant metastases | Cumulative incidence of distant metastases | 3 Years | 
| Overall survival | Overall survival | 3 years | 
| Translational / biomarker studies | The translational research program will include proteomics, genomics and immune profile assessment in primary tumor samples as well as peripheral bloods samples (liquid biopsy). Tumor tissue samples and blood will be collected, processed and stored using protocols. Primary tumor tissue with either fresh tissue or formalin-fixed, paraffin-embedded (FFPE) tissue will be collected at two different time points: i) preoperative biopsy; ii) before/during surgical resection. Peripheral blood samples will be stored at three different time points: i) immediately before initiation of preoperative treatment (day 1); ii) during therapy assessment at week 22-24 and iii) at the time point of the first follow up. | 3 years |