Short-course Radiotherapy Versus Chemoradiotherapy, Followed by Consolidation Chemotherapy, and Selective Organ Preservation for MRI-defined Intermediate and High-risk Rectal Cancer Patients
Overview
- Phase
- Phase 3
- Intervention
- Oxaliplatin, 85 mg/m2
- Conditions
- Rectal Cancer Stage III
- Sponsor
- Prof. Dr. med. Claus Rödel
- Enrollment
- 702
- Locations
- 76
- Primary Endpoint
- organ preservation
- Status
- Active, Not Recruiting
- Last Updated
- 2 years ago
Overview
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.
Investigators
Prof. Dr. med. Claus Rödel
Prof. Dr. med.
Goethe University
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+)
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
Arms & Interventions
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.
Intervention: Oxaliplatin, 85 mg/m2
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.
Intervention: 5FU; 2400 mg/m2
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.
Intervention: Folinic Acid, 400 mg/m2
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.
Intervention: Capecitabine, 1000 mg/m2
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.
Intervention: Oxaliplatin, 130 mg/m2
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.
Intervention: 5FU, 250 mg/m2
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.
Intervention: 5FU, 2400 mg/m2
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.
Intervention: Oxaliplatin 50 mg/m2
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.
Intervention: Folinic Acid, 400 mg/m2
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.
Intervention: Capecitabine, 1000 mg/m2
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.
Intervention: Oxaliplatin 85 mg/m2
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.
Intervention: Capecitabine, 825 mg/m2
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.
Intervention: Oxaliplatin, 130 mg/m2
Outcomes
Primary Outcomes
organ preservation
Time Frame: 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 Outcomes
- Rate of immediate TME after TNT(3 years)
- Quality of TME according to MERCURY(3 years)
- Acute and late toxicity assessment according to NCI CTCAE V.5.0) CTCAE V.5.0)(3 Yeears)
- Quality of life C30 based on treatment arm and surgical procedures/organ preservation(3 years)
- functional outcome based on treatment arm and surgical procedures/organ preservation(3 years)
- Quality of life CR29 based on treatment arm and surgical procedures/organ preservation(3 years)
- Quality of life CPIN 20 based on treatment arm and surgical procedures/organ preservation(3 years)
- Cumulative incidence of distant metastases(3 Years)
- Overall survival(3 years)
- Disease-free survival(3 years)
- Rate of clinical complete response after TNT:(3 years)
- Cumulative incidence of locoregional regrowth after cCR(3 years)
- Rate of salvage surgery (LE/TME with or APR/stoma) after locoregional regrowth APR/stoma) after locoregional regrowth(3 years)
- Cumulative incidence of local recurrence after (salvage) surgery surgery(3 years)
- Postoperative complications of (salvage) surgery(3 years)
- Rate of sphincter-sparing (salvage) surgery(3 years)
- Pathological TNM-staging(3 years)
- R0 resection rate; negative circumferential resection rate(3 years)
- Tumor regression grading according to Dworak(3 years)
- Neoadjuvant rectal score(3 years)
- Translational / biomarker studies(3 years)