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

October 7, 2024 updated by: Perivoliotis Konstantinos, Larissa University Hospital
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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

84

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Konstantinos Perivoliotis, MD
  • Phone Number: 0030 2413501000
  • Email: kperi19@gmail.com

Study Contact Backup

Study Locations

  • Greece
      • Larissa, Greece, 41110
        • Recruiting
        • Department of Surgery, University Hospital of Larissa
        • Sub-Investigator:
          • Ioannis Samaras, MD
        • Sub-Investigator:
          • Athanasios Kotsakis, Prof
        • Sub-Investigator:
          • Georgios Kyrgias, Prof
        • Contact:
          • Konstantinos Perivoliotis, MD
          • Phone Number: 00302413501000
          • Email: kperi19@gmail.com
        • Contact:
        • Principal Investigator:
          • Konstantinos Perivoliotis, MD
        • Sub-Investigator:
          • Ioannis Baloyiannis, Prof

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Neoadjuvant Chemoradiotherapy and Consolidation Chemotherapy

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
5-week neoadjuvant radiotherapy regimen (28 x 1.8 Gy) combined with Capecitabine (bid 800 mg/m2, twice daily, on days 1-33-38)
Other Names:
  • nCRT
Drug: Consolidation Chemotherapy
CAPOX (Capecitabine bid1000 mg/m2 and Oxaliplatin 130 mg/m2, day 1, every 3 weeks) or alternatively FOLFOX
Other Names:
  • CC
Active Comparator: Neoadjuvant Chemoradiotherapy and Adjuvant Chemotherapy
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
5-week neoadjuvant radiotherapy regimen (28 x 1.8 Gy) combined with Capecitabine (bid 800 mg/m2, twice daily, on days 1-33-38)
Other Names:
  • nCRT
Drug: Adjuvant Chemotherapy
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)
Other Names:
  • AC

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease Free Survival
Time Frame: 3 years postoperatively
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
Time Frame: 1 month postoperatively
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
Time Frame: 1 month postoperatively
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
Time Frame: Maximum time frame 39 days postoperatively
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
Time Frame: 1 month postoperatively
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
Time Frame: 1 month postoperatively
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
Time Frame: 3 years postoperatively
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
Time Frame: 3 years postoperatively
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
Time Frame: 3 years postoperatively
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
Time Frame: 3 years postoperatively
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Larissa University Hospital

Investigators

  • Study Director: George Tzovaras, Prof, University Hospital Of Larissa
  • Principal Investigator: Konstantinos Perivoliotis, MD, University Hospital Of Larissa

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 30, 2022

Primary Completion (Estimated)

August 30, 2026

Study Completion (Estimated)

August 30, 2026

Study Registration Dates

First Submitted

August 9, 2022

First Submitted That Met QC Criteria

August 9, 2022

First Posted (Actual)

August 11, 2022

Study Record Updates

Last Update Posted (Actual)

October 8, 2024

Last Update Submitted That Met QC Criteria

October 7, 2024

Last Verified

October 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCCCRC

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

No plan to share individual patient data

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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