OPERA Study V3.1 - Radiation dose escalation in rectal adenocarcinoma
Research type
Research Study
Full title
European phase III study comparing, in association with neoadjuvant chemoradiotherapy, a radiation dose escalation using 2 different approaches: External Beam Radiation Therapy versus endocavitary Radiation Therapy with Contact X-Ray Brachytherapy 50 kV for patients with rectal adenocarcinoma cT2-T3 a,b < 5cm in diameter in distal and middle rectum
IRAS ID
210067
Contact name
Maeva MAURIN
Contact email
Sponsor organisation
Centre Antoine Lacassagne
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
2014-A01851-46, ID-RCB
Duration of Study in the UK
4 years, 10 months, 14 days
Research summary
The purpose of the study is to demonstrate that neoadjuvant chemoradiotherapy (radiotherapy plus chemotherapy with Capecitabine drug) in combination with a boost given with Contact X-ray Brachytherapy (CXB) is superior to the same neoadjuvant therapy plus a boost with External Beam Radiation Therapy (EBRT) in terms of rectum preservation without non salvageable local disease at 3 years post treatment start, or permanent deviating stoma. \n\n236 patients aged 18 or above suffering from cancer of the rectum at an early stage with an operable tumor of less than 5 cm large and with no evidence of lymph node spread will be enrolled. The tumor should be accessible to local treatment via CXB. \n\nThe study will take place in 25 cancer centres in 5 European countries where the Papillon machine is used for the CXB treatment. \n\nPatients will be randomly assigned to either the CXB boost or the EBRT boost treatment group. The total duration of patient participation is 36 months. After treatment and until local recurrence is seen, patients will return to the clinic every 3 months for up to 2 years to have their tumor assessments performed by Digital Rectal Examination (DRE) and rigid rectoscopy. Rectosigmoidoscopy with photos and pelvic Magnetic Resonance Imaging (MRI) will also be performed every 3 months. Endorectal ultrasound (ERUS), Computed Tomography-scanner (CT-scan) and Positron Emission Tomography (PET-CT) will optionally be performed at the same time as the MRIs.\nAt week 14 from treatment initiation, patients will be evaluated and the therapeutic management strategy (watch and wait or surgery) will be decided depending on the clinical response and MRI interpretation. In case a surgery is required, it will be performed around week 16. \nBlood tests will be carried out at baseline, at the treatment evaluation and during the follow up period as per local standards of care.\n
Summary of study results:
European phase III study comparing, in association with neoadjuvant chemoradiotherapy, a radiation dose escalation using 2 different approaches: External Beam Radiation Therapy versus endocavitary Radiation Therapy with Contact X-Ray Brachytherapy 50 kV for patients with rectal adenocarcinoma cT2-T3 a,b < 5cm in diameter in distal and middle rectum
IRAS Project ID: 210067
ClinicalTrials.gov Identifier : NCT02505750Plain language Title :
European Phase III Study Comparing Two Radiation Therapy Methods (External Beam vs. Contact X-Ray Brachytherapy) Along with Chemoradiotherapy for Patients with Small Rectal Cancer TumorsWho carried out the research?
The OPERA trial was sponsored and coordinated by the Antoine Lacassagne Center in Nice, France, under the leadership of Professor Jean Pierre Gerard. The trial in the UK was overseen by Professor Sun Myint at the Clatterbridge Cancer Centre. The study received funding from the from the French government's clinical hospital research program (PHRC), Clatterbridge Cancer Centre NHS Foundation, Ariane Medical Systems, ORLAM association, and the ICONE Foundation. For more information, you can contact Professor Sun Myint at the Clatterbridge Cancer Centre.
What public involvement was in the study?
The trial involved 148 patients from France, the UK, and Switzerland, all aged 18 and above with early-stage rectal cancer. Public involvement was crucial as these patients underwent specific treatments and assessments, providing valuable data for evaluating new cancer treatments.
Participants were put into 2 groups by chance (randomized) to reduce differences between the groups. Putting people into groups by chance helps to make the 2 groups equal. Reducing differences between the groups in this way, ensure fair comparisons between the groups.
Where and when did the study take place?
The OPERA trial was conducted at 19 institutions in Europe, including France, the UK, and Switzerland. Patient enrollment occurred from June 24, 2015, to July 1, 2020. Follow-up in the UK concluded on July 7, 2023, while it will continue in France until June 24, 2030.
Why was the research needed?
This research aimed to explore alternatives to radical surgery for rectal cancer, which often results in permanent stoma or poor bowel function. By investigating the effectiveness of combining contact X-ray brachytherapy (CXB) with standard neoadjuvant chemoradiotherapy (nCRT), the study hoped to improve organ preservation and reduce the need for radical surgery.
What were the main questions studied?
The trial investigated whether adding a CXB boost to nCRT improves organ preservation in rectal cancer patients compared to an external beam radiotherapy (EBRT) boost. It also assessed the safety, effectiveness, and potential side effects of these treatments.
Who participated in the study?
A total of 148 patients with early-stage rectal cancer participated in the study, with a median age of 69 years. Seven patients withdrew their consent: four before starting treatment and three after. This left 141 patients for the main analysis, with 69 in Group A and 72 in Group B. The group included 87 men and 54 women. All participants had tumors smaller than 5 cm that could be operated on, and their cancer had not spread to the lymph nodes..
What treatments did the participants receive?
Participants were divided into two groups:
• Group A (69 patients): Received standard EBRT over 5 weeks (total dose of 45 Gy) with chemotherapy (capecitabine) following by an EBRT boost of 9 Gy over 1 weeks.
• Group B (72 patients): Received a CXB boost (90 Gy over 4 weeks) before or after standard EBRT with chemotherapy (capecitabine) for 5 weeks, depending on tumor size.
What medical problems (adverse reactions) did the participants have?
Side effects are unwanted medical events that happen during the study and are reported because the trial doctor (investigator) beliveves the side effects were related to the treatements in the trials. The two treatments were evaluated for safety by recording the number of occurrences of adverse events.
Mild to severe early treatment-related side effects were reported in 57 patients (40%), with 25 patients (36%) in Group A and 32 patients (44%) in Group B. The main side effects were inflammation of the rectum due to external beam radiation therapy (EBRT) and blood disorder or other issues related to chemotherapy and radiation therapy (CRT). Other common side effects included gastrointestinal problems and urinary issues. There were no life-threatening side effects or deaths related to the treatments.What happened during the study?
Patients underwent neoadjuvant chemoradiotherapy in combination with either a CXB or EBRT boost. The primary goal was organ preservation without non-salvageable local disease or permanent stoma at 3 years. Follow-up assessments included physical exams, rectoscopies, MRI, and optional CT or PET-CT scans. Patients were evaluated for response at weeks 14, 20, and / or 24, with treatment decisions based on these assessments.
Overall, the study demonstrated that adding CXB to the treatment regimen could improve organ preservation rates in rectal cancer patients, offering a potential alternative to radical surgery.
What were the results of the study?
The OPERA study, with a median follow-up of 48.2 months, showed that combining CXB with chemoradiotherapy improved outcomes for rectal cancer patients. Key findings include:
• Clinical Complete Response (cCR) Rates: At week 14, 41.5% in Group A (EBRT Boost) vs. 51.5% in Group B (CXB boost). When pooled with near-complete response (ncCR), the rates were 61.5% for Group A and 87.9% for Group B.
• Organ Preservation Rate: 3-year organ preservation was 59% for Group A and 81% for Group B. For tumors smaller than 3 cm, it was 63% for Group A and 97% for Group B.
• Local Recurrence: 23% in Group A vs. 15% in Group B at three years.
• Survival Rates: 3-year overall survival was 98% in both groups. Disease-free survival was 83% for Group A and 82% for Group B.
How has this study helped patients and researchers?
The study has significantly contributed to patient care and the scientific community by:
• Demonstrating that a CXB boost can improve organ preservation without increasing toxicity.
• Providing clinical guidance for integrating CXB in treatment regimens, offering an alternative to radical surgery for early rectal cancers.
• Highlighting new treatment protocols combining CXB with chemoradiotherapy for better outcomes in rectal cancer treatment.
• Establishing a research foundation for future studies, such as the TRESOR study, to further explore and refine organ preservation strategies in rectal cancer.
In France, CXB combined with chemoradiotherapy with planned organ preservation for tumors ≤ 3 cm has been recognized as a treatment option by the French society of gastroenterology.
Details of any further research planned
Future research includes:
• TRESOR Study: Initiated in France in 2023, a phase III trial in France evaluating CXB and total neoadjuvant therapy (TNT) for larger tumors (>3.5 cm) with a focus on organ preservation.
• OPAXX Trial: A planned trial in the Netherlands to investigate CXB in advanced T3 rectal cancers.
• Long-Term Follow-Up: The OPERA trial will continue to provide long-term results at 5 and 10 years to offer more comprehensive data on response durability and organ preservation.REC name
North West - Liverpool Central Research Ethics Committee
REC reference
16/NW/0828
Date of REC Opinion
16 Jan 2017
REC opinion
Further Information Favourable Opinion