Neoadjuvant Chemoradiotherapy and Consolidation Chemotherapy for Rectal Cancer: A Randomized Controlled Trial

Study Overview
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Brief Summary
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The purpose of this protocol is to compare neoadjuvant chemoradiation plus consolidation chemotherapy before surgical resection with the standard neoadjuvant chemoradiation followed by surgical resection and adjuvant chemotherapy in patients with rectal cancer.

Detailed Description
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Colorectal cancer is the second leading cause of cancer-related deaths worldwide. It is estimated that 10% of cancer mortality is attributed to malignant neoplasms of the colon and rectum. More specifically, in the United States alone, 53,200 colorectal cancer deaths were reported. The current treatment of choice for locally advanced rectal cancer (Stage II/ III) is the combination of neoadjuvant chemoradiation followed by radical surgical resection based on the principles of total mesorectal excision (TME) after a 8-12 weeks period. Therapy is usually completed with the administration of adjuvant chemotherapy based on oxaliplatin and fluoropyrimidines. This combined approach allowed the reduction of local recurrence at levels around 5%. Despite the impressive results in local control, the same was not confirmed for the long-term, overall survival. Possible explanations to that are: a) the compliance and completion of the treatment schemes during the postoperative period were low and b) there was a delay in the administration of adjuvant chemotherapy; both could lead to subclinical metastatic disease progression. On the basis of achieving both goals, (i.e., local control through neoadjuvant radiotherapy and metastatic disease control through systemic chemotherapy) the administration of the two therapies in the preoperative period was proposed, in the form of combined or total neoadjuvant therapy. Additional theoretical benefits of total neoadjuvant therapy is faster defunctioning stoma reversal, as well as, the possibility of a more accurate evaluation of the tumor biological behavior, thus enabling a safer staging for patients who would be candidates for a watch and wait protocol. Furthermore, for patients who will eventually undergo surgery, total neoadjuvant therapy could probably increase R0 resection and sphincter-preservation rates. However, many researchers question the safety and efficacy of total neoadjuvant therapy. First, the administration of neoadjuvant chemotherapy significantly increases the risk of severe toxicity from cytotoxic agents. At the same time, according to the results of one of the largest prospective randomized trials, the addition of neoadjuvant chemotherapy into the treatment algorithm did not offer any advantage in the pathological response, 5-year overall and disease-free survival rates. Finally, there is considerable heterogeneity in the current literature, most likely reflecting the different schemes used in different trials regarding the radiotherapy regimen, the chemotherapy regimen as well as the sequence of each one in each protocol. The investigators believe that it is difficult to interpret any differences in results when multiple parameters have been changed in a comparative trial. For this reason when testing the current standard neoadjuvant protocol to the new trend of total neoadjuvant therapy it was decided to keep the same scheme and timing for the experimental group while the only parameter which was different was the use of the classic chemotherapy scheme during the waiting period following chemoradiation and before surgery.

Official Title
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Neoadjuvant Chemoradiotherapy and Consolidation Chemotherapy for Rectal Cancer: A Randomized Controlled Trial

Conditions
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Rectal Neoplasms

Intervention / Treatment
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* Radiation: Neoadjuvant Chemoradiotherapy
* Drug: Adjuvant Chemotherapy
* Drug: Consolidation Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed rectal adenocarcinoma cT3, cT4, threatened CRM / MRF, EMVI (+), ≥N1 Multidisciplinary tumor board decision for neoadjuvant treatment Tumor distance from the anal verge <15 cm based on endoscopy or magnetic resonance imaging Patient 18 to 80 years old General health condition status WHO 0-1 Absence of co-morbidities that may affect treatment Neutrophils >1,500 / mm3, platelets >100,000 / mm3, hemoglobin> 10 g / dL, normal creatinine, and creatinine clearance> 50 mL / min Signed informed consent of the patient Exclusion Criteria: Distant metastases Non-resectable cancer Contraindications for the administration of chemotherapy Previous pelvic radiotherapy or chemotherapy History of inflammatory bowel disorders History of angina, acute myocardial infarction or heart failure Active sepsis or systemic infection Untreated physical and mental disability Synchronous malignancy Pregnancy or breast-feeding Lack of compliance with the protocol process Non-granting of signed informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: The study will employ a prospective, parallel randomized-controlled design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant Chemoradiotherapy and Consolidation Chemotherapy<br>The experimental group will receive the standard 5-week neoadjuvant chemoradiotherapy (CRT). Thereafter, all patients will commence consolidation chemotherapy. At the 6th week after the end of CRT, patients will undergo MRI re-staging: In case of non-response (mrTRG 5) they will be submitted immediately to surgery, and, subsequently, excluded from the trial. In case of response (mrTRG 2-4) they will receive consolidation chemotherapy for the whole waiting period between the end of CRT and surgery - 12 weeks. | Radiation: Neoadjuvant Chemoradiotherapy<br>* 5-week neoadjuvant radiotherapy regimen (28 x 1.8 Gy) combined with Capecitabine (bid 800 mg/m2, twice daily, on days 1-33-38)<br>* Other names: nCRT;Drug: Consolidation Chemotherapy<br>* CAPOX (Capecitabine bid1000 mg/m2 and Oxaliplatin 130 mg/m2, day 1, every 3 weeks) or alternatively FOLFOX<br>* Other names: CC;|
| Active Comparator: Neoadjuvant Chemoradiotherapy and Adjuvant Chemotherapy<br>The control group will receive the standard 5-week neoadjuvant chemoradiotherapy regimen. Six weeks after completion the patient will be re-staged with rectal MRI and depending on the response will be operated (TME): immediately in case of non-response (mrTRG 5) or after an additional 6-week delay (overall 12 weeks after the end of chemoradiotherapy) in case of partial response (mrTRG 2-4). Adjuvant chemotherapy will be, also, administered. | Radiation: Neoadjuvant Chemoradiotherapy<br>* 5-week neoadjuvant radiotherapy regimen (28 x 1.8 Gy) combined with Capecitabine (bid 800 mg/m2, twice daily, on days 1-33-38)<br>* Other names: nCRT;Drug: Adjuvant Chemotherapy<br>* 8 cycles of CAPOX (Capecitabine bid 1000 mg/m2, twice daily, day 1-14, every 3 weeks and Oxaliplatin 130 mg/m2, day 1, every 3 weeks) or alternatively, 12 cycles of folinate, fluorouracil and oxaliplatin (FOLFOX)<br>* Other names: AC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival | Occurence of Disease Free Survival. If such an episode occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO' | 3 years postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Pathological Response | Occurence of Complete Pathological Response. If such an episode occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO' | 1 month postoperatively | 
| Postoperative Complication | Occurence of postoperative complications based on the Clavien Dindo Classification. If such an episode occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO' | 1 month postoperatively | 
| Length of Hospital Stay | Postoperative time that the patient can be safely discharged. Measurement unit: days. The patient will be discharged, when it is ensured that is medically safe to be released. In particular, as the exit time of the patient, will be regarded the time that the patient will fulfil the Clinical Discharge Criteria | Maximum time frame 39 days postoperatively | 
| Readmission | Occurence of postoperative readmission. If such an episode occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO' | 1 month postoperatively | 
| Negative Resection Margin | Occurence of Negative Resection Margin. If such an episode occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO' | 1 month postoperatively | 
| Overall Survival | Occurence of Overall Survival. If such an episode occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO' | 3 years postoperatively | 
| Chemotherapy Toxicity | Occurence of Chemotherapy Toxicity. If such an episode occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO' | 3 years postoperatively | 
| Local Recurrence | Occurence of Local Recurrence. If such an episode occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO' | 3 years postoperatively | 
| Treatment Compliance | Occurence of Treatment Compliance. If such an episode occurs, then it will be defined as=1 'YES' If such an episode does not occur, then it will be defined as=0 'NO' | 3 years postoperatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal, cancer, neoadjuvant, radiotherapy, chemotherapy, mesorectal, excision