Short RT Versus RCT,Followed by Chemo.and Organ Preservation for Interm and High-risk Rectal Cancer Patients
- Conditions
- Rectal Cancer Stage III
- Interventions
- Drug: Oxaliplatin, 85 mg/m2Drug: 5FU, 250 mg/m2Drug: 5FU; 2400 mg/m2Drug: 5FU, 2400 mg/m2Drug: Folinic Acid, 400 mg/m2Drug: Capecitabine, 1000 mg/m2Drug: Oxaliplatin, 130 mg/m2Drug: Capecitabine, 825 mg/m2
- Registration Number
- NCT04246684
- Lead Sponsor
- Prof. Dr. med. Claus Rödel
- Brief 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 702
- 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
- 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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control arm Oxaliplatin, 85 mg/m2 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. Control arm 5FU; 2400 mg/m2 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. Control arm Folinic Acid, 400 mg/m2 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. Control arm Capecitabine, 1000 mg/m2 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. Control arm Oxaliplatin, 130 mg/m2 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. Experimental arm 5FU, 250 mg/m2 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. Experimental arm 5FU, 2400 mg/m2 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. Experimental arm Oxaliplatin 50 mg/m2 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. Experimental arm Folinic Acid, 400 mg/m2 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. Experimental arm Capecitabine, 1000 mg/m2 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. Experimental arm Oxaliplatin 85 mg/m2 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. Experimental arm Capecitabine, 825 mg/m2 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. Experimental arm Oxaliplatin, 130 mg/m2 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.
- Primary Outcome Measures
Name Time Method organ preservation 3 years 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.
- Secondary Outcome Measures
Name Time Method Rate of immediate TME after TNT 3 years TNT total neoadjuvant therapy TME total mesorectal excision
Quality of TME according to MERCURY 3 years Tumor response using MRI scale 1-5 from good to poor descending
Acute and late toxicity assessment according to NCI CTCAE V.5.0) CTCAE V.5.0) 3 Yeears CTCAE V.5.0
Quality of life C30 based on treatment arm and surgical procedures/organ preservation 3 years Quality of life based on EORTC-QLQs-C30
functional outcome based on treatment arm and surgical procedures/organ preservation 3 years functional outcome based on Wexner score
Quality of life CR29 based on treatment arm and surgical procedures/organ preservation 3 years Quality of life based on EORTC-QLQs-CR29
Quality of life CPIN 20 based on treatment arm and surgical procedures/organ preservation 3 years Quality of life based on EORTC-QLQs-CPIN20 Quality of life based on EORTC-QLQs-CPIN20
Cumulative incidence of distant metastases 3 Years Cumulative incidence of distant metastases
Overall survival 3 years Overall survival
Disease-free survival 3 years Disease-free survival
Rate of clinical complete response after TNT: 3 years TNT total neoadjuvant therapy
Cumulative incidence of locoregional regrowth after cCR 3 years cCR clinical complete response
Rate of salvage surgery (LE/TME with or APR/stoma) after locoregional regrowth APR/stoma) after locoregional regrowth 3 years LE local Exision; TME: Transanale endoscopic Mikrochirurgie; APR Abdomino perineal Rectum exstirpation
Cumulative incidence of local recurrence after (salvage) surgery surgery 3 years Cumulative incidence of local recurrence after (salvage) surgery
Postoperative complications of (salvage) surgery 3 years Postoperative complications of (salvage) surgery
Rate of sphincter-sparing (salvage) surgery 3 years Rate of sphincter-sparing (salvage) surgery
Pathological TNM-staging 3 years Pathological tumor evaluations;TNM tumor staging
R0 resection rate; negative circumferential resection rate 3 years R0 Removal of the tumor in healthy tissue
Tumor regression grading according to Dworak 3 years pathological response from scale 1-4 poor to very good ascending
Neoadjuvant rectal score 3 years Neoadjuvant rectal score from low to high values means good to poor
Translational / biomarker studies 3 years 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.
Trial Locations
- Locations (76)
University Clinic Erlangen
🇩🇪Erlangen, Bavaria, Germany
Technical University Munich
🇩🇪München, Bavaria, Germany
Klinikverbund Allgäu
🇩🇪Kempten, Bavaria, Germany
Clincal Center Helios Bad Saarrow
🇩🇪Bad Saarow, Brandenburg, Germany
MVZ Oncological Cooperation Harz
🇩🇪Goslar, Lower Saxony, Germany
Clinic Wolfsburg
🇩🇪Wolfsburg, Lower Saxony, Germany
Hematological-Oncological Practice Dr. Oleg Rubanov, Hameln
🇩🇪Hameln, Lower Saxony, Germany
Sana Clinical Center Offenbach
🇩🇪Offenbach, Hessen, Germany
Technical University Clinic Munich
🇩🇪München, Bavaria, Germany
Clinic Bayreuth GmbH
🇩🇪Bayreuth, Bavaria, Germany
Clincal Center Darmstadt
🇩🇪Darmstadt, Hessen, Germany
Clinic North West gGmbH Frankfurt
🇩🇪Frankfurt am Main, Hessen, Germany
Medius Clincal Center Ostfildern-Ruit
🇩🇪Ostfildern, Baden-Wuerttemberg, Germany
Lahn-Dill Clinics Wetzlar
🇩🇪Wetzlar, Hessen, Germany
DRK Clincal Centers North Hessen Kassel
🇩🇪Kassel, Hessen, Germany
Clinic Nordoberpfalz AG, Clinic Weiden
🇩🇪Weiden, Bavaria, Germany
Clincal Center Esslingen
🇩🇪Esslingen, Baden-Wuerttemberg, Germany
Pi.Tri-Studien GmbH, Offenburg
🇩🇪Offenburg, Baden-Wuerttemberg, Germany
University Clinic Marburg
🇩🇪Marburg, Hessen, Germany
Clincal Center "Bogenhausen" Munich
🇩🇪München, Bavaria, Germany
Hospital "Barmherzige Brüder" Regensburg
🇩🇪Regensburg, Bavaria, Germany
University Clinic Ulm
🇩🇪Ulm, Baden-Wuerttemberg, Germany
University Clinic Mannheim
🇩🇪Mannheim, Baden-Wuerttemberg, Germany
Clincal Center "St. Marien" Amberg
🇩🇪Amberg, Bavaria, Germany
"St. Bernward" Clincal Center Hildesheim
🇩🇪Hildesheim, Lower Saxony, Germany
Ev. Waldkrankenhaus, Spandau,
🇩🇪Berlin, Germany
Oncology Practice Dresden
🇩🇪Dresden, Saxony, Germany
Clincal Center Chemnitz
🇩🇪Chemnitz, Saxony, Germany
Franziskus Hospital Bielefeld
🇩🇪Bielefeld, North Rhine-Westphalia, Germany
St. Vincenz Hospital Paderborn
🇩🇪Paderborn, North Rhine-Westphalia, Germany
University Clinic Essen
🇩🇪Essen, North Rhine-Westphalia, Germany
Hospital Bochum
🇩🇪Bochum, North Rhine-Westphalia, Germany
CaritasClinic Saarbrücken
🇩🇪Saarbrücken, Saarland, Germany
Clinic Lippe GmbH (Lemgo/Detmold)
🇩🇪Detmold, North Rhine-Westphalia, Germany
Clinic Maria Hilf GmbH
🇩🇪Mönchengladbach, North Rhine-Westphalia, Germany
Mathias-Spital, Rheine
🇩🇪Rheine, North Rhine-Westphalia, Germany
Clinic Sankt Georg gGmbH, Leipzig
🇩🇪Leipzig, Saxony, Germany
Helios Klinikum Berlin Emil von Behring
🇩🇪Berlin, Germany
University Clinic Freiburg
🇩🇪Freiburg, Baden-Wuerttemberg, Germany
Clinic Ostlab, Staufenclinic Schwaeb.Gmuend, Mutlangen
🇩🇪Mutlangen, Baden-Wuerttemberg, Germany
University Clinic for Radioncology Tübingen
🇩🇪Tübingen, Baden-Wuerttemberg, Germany
Clinical Center Coburg
🇩🇪Coburg, Bavaria, Germany
University Clinic Würzburg
🇩🇪Würzburg, Bavaria, Germany
University Clinic Göttingen
🇩🇪Göttingen, Lower Saxony, Germany
Clinic Fulda
🇩🇪Fulda, Hessen, Germany
Medical Project Hannover
🇩🇪Hannover, Lower Saxony, Germany
Oncology in Medicinum Hildesheim
🇩🇪Hildesheim, Lower Saxony, Germany
Oncology UnterEms, Leer
🇩🇪Leer, Lower Saxony, Germany
Pius Hospital, Oldenburg
🇩🇪Oldenburg, Lower Saxony, Germany
University Clinic Rostock
🇩🇪Rostock, Mecklenburg Western Pomerania, Germany
University Clinic Oldenburg
🇩🇪Oldenburg, Lower Saxony, Germany
Clinical Center "Essen Mitte"
🇩🇪Essen, North Rhine-Westphalia, Germany
Brother clinic St. Josef, Paderborn
🇩🇪Paderborn, North Rhine Westphalia, Germany
Evangelical Clinic Wesel
🇩🇪Wesel, North Rhine Westphalia, Germany
Prosper Hospital Recklinghausen
🇩🇪Recklinghausen, North Rhine-Westphalia, Germany
University Clinic Mainz
🇩🇪Mainz, Rhineland-Palantine, Germany
Clinical Center "Mutterhaus" Trier
🇩🇪Trier, Rhineland-Palatinate, Germany
Radiotherapy Practice Dr. A. Schreiber, Dresden
🇩🇪Dresden, Saxony, Germany
University Clinic Magdeburg
🇩🇪Magdeburg, Saxony-Anhalt, Germany
University Clinic Leipzig
🇩🇪Leipzig, Saxony, Germany
Vivantes Clincial Center in Friedrichshain
🇩🇪Berlin, Germany
University Clinic Kiel
🇩🇪Kiel, Schleswig-Holstein, Germany
Klinikum Bielefeld
🇩🇪Bielefeld, Germany
Praxis für Hämatologie und Onkologie
🇩🇪Gießen, Germany
Department of Radiooncology
🇩🇪Frankfurt, Germany
Universitätsklinikum Halle
🇩🇪Halle (Saale), Germany
Alexianer Krefeld GmbH / Maria Hilf Krankenhaus
🇩🇪Krefeld, Germany
Uniklinik Schleswig Holstein
🇩🇪Luebeck, Germany
Med. Statistik Saarbrücken GgR
🇩🇪Saarbruecken, Germany
Schwarzwald-Baar-Kliniken
🇩🇪Villingen-Schwenningen, Germany
Clincal Center Helios Berlin Buch
🇩🇪Berlin, Germany
Onkologische Schwerpunktpraxis
🇩🇪Darmstadt, Germany
Clinic Stuttgart
🇩🇪Stuttgart, Baden-Wuerttemberg, Germany
St. Josef Hospital of the catholic clinic Bochum
🇩🇪Bochum, North Rhine Westphalia, Germany
Dietrich Bonhoeffer Klinik
🇩🇪Neubrandenburg, Germany
University Clinic Regensburg
🇩🇪Regensburg, Bavaria, Germany