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

Short-course Radiotherapy Versus Chemoradiotherapy, Followed by Consolidation Chemotherapy, and Selective Organ Preservation for MRI-defined Intermediate 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Rectal Cancer Stage III
• Intervention / Treatment: Drug: Oxaliplatin, 85 mg/m2; Drug: 5FU; 2400 mg/m2; Drug: Folinic Acid, 400 mg/m2; Radiation: Radiotherapy control, 5x5 Gy: 25 Gy; Drug: Capecitabine, 1000 mg/m2; Drug: Oxaliplatin, 130 mg/m2; Drug: 5FU, 250 mg/m2; Drug: 5FU, 2400 mg/m2; Drug: Oxaliplatin 50 mg/m2; Drug: Oxaliplatin 85 mg/m2; Radiation: radiotherapy experimental, 30 x 1,8 Gy: 54 Gy; Drug: Capecitabine, 825 mg/m2

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.

• Study Type: Interventional
• Enrollment (Actual): 702
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10249
    • Vivantes Clincial Center in Friedrichshain
  • Berlin, Germany, 13125
    • Clincal Center Helios Berlin Buch
  • Berlin, Germany, 13589
    • Ev. Waldkrankenhaus, Spandau,
  • Berlin, Germany, 14650
    • Helios Klinikum Berlin Emil von Behring
  • Bielefeld, Germany, 33604
    • Klinikum Bielefeld
  • Darmstadt, Germany, 64287
    • Onkologische Schwerpunktpraxis
  • Frankfurt, Germany, 60590
    • Department of Radiooncology
  • Gießen, Germany, 35392
    • Praxis fur Hamatologie und Onkologie
  • Halle (Saale), Germany, 06120
    • Universitatsklinikum Halle
  • Krefeld, Germany, 47805
    • Alexianer Krefeld GmbH / Maria Hilf Krankenhaus
  • Luebeck, Germany, 23538
    • Uniklinik Schleswig Holstein
  • Neubrandenburg, Germany, 17036
    • Dietrich Bonhoeffer Klinik
  • Saarbruecken, Germany, 66113
    • Med. Statistik Saarbrücken GgR
  • Villingen-Schwenningen, Germany, 78052
    • Schwarzwald-Baar-Kliniken
  • Baden-Wuerttemberg
    • Esslingen, Baden-Wuerttemberg, Germany, 73730
      • Clincal Center Esslingen
    • Freiburg, Baden-Wuerttemberg, Germany, 79106
      • University clinic Freiburg
    • Mannheim, Baden-Wuerttemberg, Germany, 68167
      • University Clinic Mannheim
    • Mutlangen, Baden-Wuerttemberg, Germany, 73557
      • Clinic Ostlab, Staufenclinic Schwaeb.Gmuend, Mutlangen
    • Offenburg, Baden-Wuerttemberg, Germany, 77654
      • Pi.Tri-Studien GmbH, Offenburg
    • Ostfildern, Baden-Wuerttemberg, Germany, 73760
      • Medius Clincal Center Ostfildern-Ruit
    • Stuttgart, Baden-Wuerttemberg, Germany, 70174
      • Clinic Stuttgart
    • Tübingen, Baden-Wuerttemberg, Germany, 72076
      • University Clinic for Radioncology Tübingen
    • Ulm, Baden-Wuerttemberg, Germany, 89081
      • University Clinic Ulm
  • Bavaria
    • Amberg, Bavaria, Germany, 92224
      • Clincal Center "St. Marien" Amberg
    • Bayreuth, Bavaria, Germany, 95445
      • Clinic Bayreuth GmbH
    • Coburg, Bavaria, Germany, 96450
      • Clinical Center Coburg
    • Erlangen, Bavaria, Germany, 91054
      • University Clinic Erlangen
    • Kempten, Bavaria, Germany, 87439
      • Klinikverbund Allgäu
    • München, Bavaria, Germany, 81675
      • Technical University Clinic Munich
    • München, Bavaria, Germany, 81675
      • Technical University Munich
    • München, Bavaria, Germany, 81925
      • Clincal Center "Bogenhausen" Munich
    • Regensburg, Bavaria, Germany, 93046
      • Hospital "Barmherzige Brüder" Regensburg
    • Regensburg, Bavaria, Germany, 93053
      • University Clinic Regensburg
    • Weiden, Bavaria, Germany, 92637
      • Clinic Nordoberpfalz AG, Clinic Weiden
    • Würzburg, Bavaria, Germany, 97080
      • University Clinic Würzburg
  • Brandenburg
    • Bad Saarow, Brandenburg, Germany, 15526
      • Clincal Center Helios Bad Saarrow
  • Hessen
    • Darmstadt, Hessen, Germany, 64283
      • Clincal Center Darmstadt
    • Frankfurt am Main, Hessen, Germany, 60488
      • Clinic North West gGmbH Frankfurt
    • Fulda, Hessen, Germany, 36043
      • Clinic Fulda
    • Kassel, Hessen, Germany, 34121
      • DRK Clincal Centers North Hessen Kassel
    • Marburg, Hessen, Germany, 35043
      • University Clinic Marburg
    • Offenbach, Hessen, Germany, 63069
      • Sana Clinical Center Offenbach
    • Wetzlar, Hessen, Germany, 35578
      • Lahn-Dill Clinics Wetzlar
  • Lower Saxony
    • Goslar, Lower Saxony, Germany, 38642
      • MVZ Oncological Cooperation Harz
    • Göttingen, Lower Saxony, Germany, 37075
      • University Clinic Göttingen
    • Hameln, Lower Saxony, Germany, 31785
      • Hematological-Oncological Practice Dr. Oleg Rubanov, Hameln
    • Hannover, Lower Saxony, Germany, 30171
      • Medical Project Hannover
    • Hildesheim, Lower Saxony, Germany, 31134
      • "St. Bernward" Clincal Center Hildesheim
    • Hildesheim, Lower Saxony, Germany, 31135
      • Oncology in Medicinum Hildesheim
    • Leer, Lower Saxony, Germany, 26789
      • Oncology UnterEms, Leer
    • Oldenburg, Lower Saxony, Germany, 25121
      • Pius Hospital, Oldenburg
    • Oldenburg, Lower Saxony, Germany, 26133
      • University Clinic Oldenburg
    • Wolfsburg, Lower Saxony, Germany, 38440
      • Clinic Wolfsburg
  • Mecklenburg Western Pomerania
    • Rostock, Mecklenburg Western Pomerania, Germany, 18059
      • University Clinic Rostock
  • North Rhine Westphalia
    • Bochum, North Rhine Westphalia, Germany, 44791
      • St. Josef Hospital of the catholic clinic Bochum
    • Paderborn, North Rhine Westphalia, Germany, 33098
      • Brother clinic St. Josef, Paderborn
    • Wesel, North Rhine Westphalia, Germany, 46485
      • Evangelical Clinic Wesel
  • North Rhine-Westphalia
    • Bielefeld, North Rhine-Westphalia, Germany, 33615
      • Franziskus Hospital Bielefeld
    • Bochum, North Rhine-Westphalia, Germany, 44892
      • Hospital Bochum
    • Detmold, North Rhine-Westphalia, Germany, 32756
      • Clinic Lippe GmbH (Lemgo/Detmold)
    • Essen, North Rhine-Westphalia, Germany, 45122
      • University Clinic Essen
    • Essen, North Rhine-Westphalia, Germany, 45136
      • Clinical Center "Essen Mitte"
    • Mönchengladbach, North Rhine-Westphalia, Germany, 41063
      • Clinic Maria Hilf GmbH
    • Paderborn, North Rhine-Westphalia, Germany, 33098
      • St. Vincenz Hospital Paderborn
    • Recklinghausen, North Rhine-Westphalia, Germany, 45659
      • Prosper Hospital Recklinghausen
    • Rheine, North Rhine-Westphalia, Germany, 48431
      • Mathias-Spital, Rheine
  • Rhineland-Palantine
    • Mainz, Rhineland-Palantine, Germany, 55116
      • University Clinic Mainz
  • Rhineland-Palatinate
    • Trier, Rhineland-Palatinate, Germany, 54290
      • Clinical Center "Mutterhaus" Trier
  • Saarland
    • Saarbrücken, Saarland, Germany, 66113
      • CaritasClinic Saarbrücken
  • Saxony
    • Chemnitz, Saxony, Germany, 09113
      • Clincal Center Chemnitz
    • Dresden, Saxony, Germany, 01067
      • Radiotherapy Practice Dr. A. Schreiber, Dresden
    • Dresden, Saxony, Germany, 01307
      • Oncology Practice Dresden
    • Leipzig, Saxony, Germany, 04103
      • University Clinic Leipzig
    • Leipzig, Saxony, Germany, 04129
      • Clinic Sankt Georg gGmbH, Leipzig
  • Saxony-Anhalt
    • Magdeburg, Saxony-Anhalt, Germany, 39120
      • University Clinic Magdeburg
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • University Clinic Kiel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control arm; 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; 85 mg/m2,2h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapy; Other Names: Control arm; Drug: 5FU; 2400 mg/m2; 2400 mg/m2, 46h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, 134 of therapy for Control arm; Other Names: 5-FU, control arm; Drug: Folinic Acid, 400 mg/m2; 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; Other Names: Folinic Acid; Radiation: Radiotherapy control, 5x5 Gy: 25 Gy; Control arm: 5x5 Gy (total: 25 Gy) 5 fractions; Drug: Capecitabine, 1000 mg/m2; 1000 mg/m2 (twice daily) day1-14 every three weeks instead of 5FU optional; Other Names: Capecitabine; Drug: Oxaliplatin, 130 mg/m2; day1every three weeks (optional); Other Names: Oxaliplatin
Experimental: Experimental arm; 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: Folinic Acid, 400 mg/m2; 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; Other Names: Folinic Acid; Drug: Capecitabine, 1000 mg/m2; 1000 mg/m2 (twice daily) day1-14 every three weeks instead of 5FU optional; Other Names: Capecitabine; Drug: Oxaliplatin, 130 mg/m2; day1every three weeks (optional); Other Names: Oxaliplatin; Drug: 5FU, 250 mg/m2; 250 mg/m2 per day, civ, on day 1-14, day 22-35 of radiotherapy; Other Names: Experimental arm: 5-FU; Drug: 5FU, 2400 mg/m2; 2400 mg/m2,46h-civ, d64, d78, d92, d106, d120, d134 of therapy; Other Names: experimental arm; Drug: Oxaliplatin 50 mg/m2; 50 mg/m2, 2h-civ, d1, d8, d21, d29 of radiotherapy and; Other Names: Experimental arm; Drug: Oxaliplatin 85 mg/m2; 85 mg/m2, 2h-civ, d64, d78, d92, d106, d120, d134 of therapy; Other Names: experimental arm; Radiation: radiotherapy experimental, 30 x 1,8 Gy: 54 Gy; 30 x 1.8 Gy (total: 54 Gy), 5 fractions per week; Drug: Capecitabine, 825 mg/m2; 825 mg/m2 bid, per os, on day 1-14, 22-35 of RT instead of 5FU optional; Other Names: Capecitabine

What is the study measuring?

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
Overall survival	Overall survival	3 years
functional outcome based on treatment arm and surgical procedures/organ preservation	functional outcome based on Wexner score	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
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
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

Collaborators and Investigators

• Sponsor: Prof. Dr. med. Claus Rödel
• Investigators: Study Director: Claus Roedel, Prof. Dr., clinic for radiotherapy

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2020
• Primary Completion (Actual): September 15, 2023
• Study Completion (Estimated): September 15, 2028

Study Registration Dates

• First Submitted: January 23, 2020
• First Submitted That Met QC Criteria: January 28, 2020
• First Posted (Actual): January 29, 2020

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 17, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Capecitabine; Oxaliplatin; Leucovorin; Levoleucovorin; Folic Acid
• Other Study ID Numbers: ACO/ARO/AIO-18.1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No