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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
702
85 mg/m2,2h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, and 134 of therapy
2400 mg/m2, 46h-civ, day 22, 36, 50, 64, 78, 92, 106, 120, 134 of therapy for Control arm
250 mg/m2 per day, civ, on day 1-14, day 22-35 of radiotherapy;
2400 mg/m2,46h-civ, d64, d78, d92, d106, d120, d134 of therapy
50 mg/m2, 2h-civ, d1, d8, d21, d29 of radiotherapy and
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
Control arm: 5x5 Gy (total: 25 Gy) 5 fractions
1000 mg/m2 (twice daily) day1-14 every three weeks instead of 5FU optional
85 mg/m2, 2h-civ, d64, d78, d92, d106, d120, d134 of therapy
30 x 1.8 Gy (total: 54 Gy), 5 fractions per week
825 mg/m2 bid, per os, on day 1-14, 22-35 of RT instead of 5FU optional
day1every three weeks (optional)
Clincal Center Esslingen
Esslingen am Neckar, Baden-Wurttemberg, Germany
University Clinic Freiburg
Freiburg im Breisgau, Baden-Wurttemberg, Germany
University Clinic Mannheim
Mannheim, Baden-Wurttemberg, Germany
Clinic Ostlab, Staufenclinic Schwaeb.Gmuend, Mutlangen
Mutlangen, Baden-Wurttemberg, Germany
Pi.Tri-Studien GmbH, Offenburg
Offenburg, Baden-Wurttemberg, Germany
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.
Time frame: 3 years
Disease-free survival
Disease-free survival
Time frame: 3 years
Rate of clinical complete response after TNT:
TNT total neoadjuvant therapy
Time frame: 3 years
Rate of immediate TME after TNT
TNT total neoadjuvant therapy TME total mesorectal excision
Time frame: 3 years
Cumulative incidence of locoregional regrowth after cCR
cCR clinical complete response
Time frame: 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
Time frame: 3 years
Cumulative incidence of local recurrence after (salvage) surgery surgery
Cumulative incidence of local recurrence after (salvage) surgery
Time frame: 3 years
Postoperative complications of (salvage) surgery
Postoperative complications of (salvage) surgery
Time frame: 3 years
Rate of sphincter-sparing (salvage) surgery
Rate of sphincter-sparing (salvage) surgery
Time frame: 3 years
Pathological TNM-staging
Pathological tumor evaluations;TNM tumor staging
Time frame: 3 years
R0 resection rate; negative circumferential resection rate
R0 Removal of the tumor in healthy tissue
Time frame: 3 years
Tumor regression grading according to Dworak
pathological response from scale 1-4 poor to very good ascending
Time frame: 3 years
Neoadjuvant rectal score
Neoadjuvant rectal score from low to high values means good to poor
Time frame: 3 years
Quality of TME according to MERCURY
Tumor response using MRI scale 1-5 from good to poor descending
Time frame: 3 years
Acute and late toxicity assessment according to NCI CTCAE V.5.0) CTCAE V.5.0)
CTCAE V.5.0
Time frame: 3 Yeears
Quality of life C30 based on treatment arm and surgical procedures/organ preservation
Quality of life based on EORTC-QLQs-C30
Time frame: 3 years
functional outcome based on treatment arm and surgical procedures/organ preservation
functional outcome based on Wexner score
Time frame: 3 years
Quality of life CR29 based on treatment arm and surgical procedures/organ preservation
Quality of life based on EORTC-QLQs-CR29
Time frame: 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
Time frame: 3 years
Cumulative incidence of distant metastases
Cumulative incidence of distant metastases
Time frame: 3 Years
Overall survival
Overall survival
Time frame: 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.
Time frame: 3 years
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Medius Clincal Center Ostfildern-Ruit
Ostfildern, Baden-Wurttemberg, Germany
Clinic Stuttgart
Stuttgart, Baden-Wurttemberg, Germany
University Clinic for Radioncology Tübingen
Tübingen, Baden-Wurttemberg, Germany
University Clinic Ulm
Ulm, Baden-Wurttemberg, Germany
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Amberg, Bavaria, Germany
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