Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation. The RAPIDO Trial (RAPIDO)

January 11, 2023 updated by: B. van Etten, MD, PhD, University Medical Center Groningen

Randomized Multicentre Phase III Study of Short Course Radiation Therapy Followed by Prolonged Pre-operative Chemotherapy and Surgery in Primary High Risk Rectal Cancer Compared to Standard Chemoradiotherapy and Surgery and Optional Adjuvant Chemotherapy.

Currently the 3-year disease free survival of patients with locally advanced rectal cancer is about 50%. Current standard treatment for patients at high risk of failing locally and/or systemically includes pre-operative long course radiotherapy (5 weeks) in combination with chemotherapy (so called neoadjuvant chemoradiotherapy). The neoadjuvant chemoradiotherapy has been demonstrated to improve local control, but had no effect on the overall survival. Different studies in patients with rectal cancer studying the effect of adjuvant post operative chemotherapy did not result in an improved survival. This may be due the fact that rectal cancer surgery (TME) is associated with a high complication rate so substantial proportion of patients cannot receive chemotherapy postoperatively. An alternative approach is to administer the systemic therapy preoperative. To guarantee control of the rectum tumor short-course radiotherapy (5 days) is given, as different studies showed local control of the tumor for a long time. During this waiting period the patient is in a good condition to receive an optimal dose of chemotherapy. The investigators hypothesize that with this proposed protocol both the local tumour and possible micrometastases are effectively treated and that this will result in an increased survival. The investigators will compare this with the standard treatment of neoadjuvant chemoradiation followed by TME surgery and optional adjuvant chemotherapy.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Patients will be randomized between an experimental group (arm B) in which short course 5 x 5 Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine/5FU and oxaliplatin) and surgery and a control group (arm A) with long course chemoradiotherapy followed by surgery. In arm A adjuvant chemotherapy is allowed according to the local protocol of the institution. In both groups the rectal tumour will be removed by TME surgery or more extensive surgery if required because of tumour extent.

Study Type

Interventional

Enrollment (Actual)

920

Phase

  • Phase 3

Contacts and Locations

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

Study Locations

  • Denmark
      • Aalborg, Denmark
        • Aalborg Universitetshospital
      • Odense, Denmark
        • Odense Universitetshospital
  • Netherlands
      • Alkmaar, Netherlands
        • Noordwest Ziekenhuisgroep
      • Amsterdam, Netherlands
        • Onze Lieve Vrouwe Gasthuis
      • Amsterdam, Netherlands
        • Amsterdam UMC, location AMC
      • Amsterdam, Netherlands
        • Amsterdam UMC, location VUmc
      • Amsterdam, Netherlands
        • Nki / Avl
      • Assen, Netherlands
        • Wilhelmina Ziekenhuis
      • Breda, Netherlands
        • Amphia Ziekenhuis
      • Delft, Netherlands
        • Reinier de Graaf Groep
      • Den Haag, Netherlands
        • Bronovo Ziekenhuis
      • Den Haag, Netherlands
        • Hagaziekenhuis
      • Den Haag, Netherlands
        • Medisch Centrum Haaglanden
      • Deventer, Netherlands
        • Deventer Hospital
      • Eindhoven, Netherlands
        • Catharina Ziekenhuis
      • Gouda, Netherlands
        • Het Groene Hart Ziekenhuis
      • Groningen, Netherlands
        • Martini Ziekenhuis
      • Groningen, Netherlands
        • Universitair Medisch Centrum Groningen
      • Heerenveen, Netherlands
        • de Tjongerschans
      • Hengelo, Netherlands
        • Ziekenhuisgroep Twente
      • Hoofddorp, Netherlands
        • Spaarne Ziekenhuis
      • Leeuwarden, Netherlands
        • Medisch Centrum Leeuwarden
      • Leeuwarden, Netherlands
        • Radiotherapeutisch Instituut Friesland
      • Leiden, Netherlands
        • Leiden University Medical Center
      • Leiderdorp, Netherlands
        • Alrijne Ziekenhuis
      • Nijmegen, Netherlands
        • UMC Nijmegen St Radboud
      • Sneek, Netherlands
        • Antonius Ziekenhuis
      • Utrecht, Netherlands
        • Diakonessenhuis
      • Zwolle, Netherlands
        • Isala Klinieken
    • Po Box 30001
      • Groningen, Po Box 30001, Netherlands, 9700 RB
        • University Medical Center Groningen
  • Norway
      • Kristiansand, Norway
        • Sørlandet Sykehus Kristiansand
      • Oslo, Norway
        • Oslo Universitetssykehus
  • Slovenia
      • Ljubljana, Slovenia
        • Institute of Oncology
  • Spain
      • Barcelona, Spain
        • Hospital Vall d'Hebron
      • L'HOSPITALET de LLOBREGAT, Spain
        • ICO Hospital Duran i Reynals
      • Valencia, Spain
        • Hospital Clinico Universitario de Valencia
      • Valencia, Spain
        • Hospital Universitari i Politècnic la Fe
      • Valencia, Spain
        • Consorcio Hospital General Universitario Valencia
  • Sweden
      • Borås, Sweden
        • Sodra Alvsborgs Sjukhus
      • Eskilstuna, Sweden
        • Mälarsjukhuset
      • Falun, Sweden
        • Falu Lasarett
      • Gävle, Sweden
        • Gavle Sjukhus
      • Göteborg, Sweden
        • Sahlgrenska Universitetssjukhuset
      • Kalmar, Sweden
        • Kalmar Hospital
      • Karlstad, Sweden
        • Centralsjukhuset i Karlstad
      • Linköping, Sweden
        • Linköpings universitet
      • Lund, Sweden
        • Universitetssjukhuset i Lund
      • Skövde, Sweden
        • Skaraborgs sjukhus
      • Stockholm, Sweden
        • Karolinska Universitetssjukhuset
      • Sundsvall, Sweden
        • Sundsvalls sjukhus
      • Umeå, Sweden
        • Norrlands Universitetssjukhus
      • Uppsala, Sweden
        • Akademiska Sjukhuset
      • Västerås, Sweden
        • Centrallasarett
      • Växjö, Sweden
        • Centrallasarettet Vaxjo
      • Örebro, Sweden
        • Universitetssjukhuset Örebro
  • United States
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Siteman Cancer Center, Washington University Medical School

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 and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Primary tumour characteristics:

  1. Histological proof of newly diagnosed primary adenocarcinoma of the rectum
  2. Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically (T4a, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side wall (according to TNM version 5), cT4b, i.e. peritoneal involvement, extramural vascular invasion (EMVI+). N2, i.e. four or more lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease. Positive MRF, i.e. tumor or lymph node < 1 mm from the mesorectal fascia. Enlarged lateral nodes, > 1 cm (lat LN+)

Exclusion Criteria:

  1. Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen
  2. Presence of metastatic disease or recurrent rectal tumour
  3. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn¡¦s disease or active ulcerative Colitis
  4. Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years
  5. Known DPD deficiency
  6. Any contraindications to MRI (e.g. patients with pacemakers)
  7. Medical or psychiatric conditions that compromise the patient's ability to give informed consent
  8. Concurrent uncontrolled medical conditions
  9. Any investigational treatment for rectal cancer within the past month
  10. Pregnancy or breast feeding
  11. Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract
  12. Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months
  13. Patients with symptoms or history of peripheral neuropathy

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: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: B: 5x5Gy -> CAPOX -> surgery
experimental group (arm B) M1 scheme
Other: M1 scheme
short course 5 x 5 Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine and oxaliplatin (CAPOX)) and surgery. FOLFOX4 may be given as alternative for CAPOX
Active Comparator: A: 5 weeks chemoradiation -> surgery
control group (arm A) standard long course chemoradiotherapy
Other: standard long course chemoradiotherapy
long course chemoradiotherapy followed by surgery. Optional adjuvant chemotherapy (CAPOX or FOLFOX) is allowed in the control group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease related Treatment Failure (DrTF)
Time Frame: 3 year follow-up after surgery
DrTF = Either local or distant relapse or death caused by the rectal carcinoma whichever comes first. In case of nonrectal cancer related death patients will be censored at date of death. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour. In case of local regrowth after wait & watch strategy, followed by no resection or R2 resection, diagnosis local regrowth is taken. Patients lost to follow-up will be censored the last date of patient visit. Survival curves for Disease related Treatment Failure after 3 years of follow-up will be constructed using the method of Kaplan and Meier.
3 year follow-up after surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: 10 year

Overall survival will be computed as the time between randomization and colorectal cancer or treatment related death. Patients lost to follow-up will be censored the last date of patient visit.

In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour.
10 year
CRM negative rate
Time Frame: within 30 days
Circumferential resection margin > 1 mm
within 30 days
pCR rate
Time Frame: within 30 days
Pathological complete response after neo-adjuvant treatment
within 30 days
Short and long-term toxicity
Time Frame: 3 year follow-up
Treatment associated toxicity
3 year follow-up
Surgical complications
Time Frame: 3 year follow-up
Wound rupture, bleeding, infection, rectal anastomotic leak
3 year follow-up
Quality of life QLQ-C30
Time Frame: 3 year after surgery
Quality of life QLQ-C30
3 year after surgery
Quality of life QLQ-CR-29+
Time Frame: 3 year after surgery
Quality of life QLQ-CR-29+
3 year after surgery
Quality of life QLQ-CIPN20
Time Frame: 3 year after surgery
Quality of life QLQ-CIPN20
3 year after surgery
Quality of life LARS
Time Frame: 3 year after surgery
LARS
3 year after surgery

Collaborators and Investigators

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

Sponsor

University Medical Center Groningen

Collaborators

Karolinska University Hospital
Leiden University Medical Center
Uppsala University Hospital
Dutch Cancer Society

Investigators

  • Principal Investigator: B. van Etten, MD, PhD, University Medical Center Groningen, Department of Surgery, Groningen, The Netherlands
  • Principal Investigator: B. Glimelius, MD, PhD, Akademiska Sjukhuset, Department of Oncology, Uppsala, Sweden
  • Principal Investigator: G. A. Hospers, MD, PhD, University Medical Center Groningen, Department of Medical Oncology, Groningen, The Netherlands
  • Principal Investigator: P. Nilsson, MD, PhD, Karolinska Universitetssjukhuset, Stockholm, Sweden
  • Principal Investigator: C. J. van de Velde, MD, PhD, Leiden University Medical Center, Department of Surgery, Leiden, The Netherlands
  • Principal Investigator: C.A.M. Marijnen, MD, PhD, Netherlands Cancer Institute, Amsterdam, the Netherlands

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

Helpful Links

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)

June 21, 2011

Primary Completion (Actual)

March 8, 2020

Study Completion (Anticipated)

December 31, 2026

Study Registration Dates

First Submitted

March 18, 2012

First Submitted That Met QC Criteria

March 19, 2012

First Posted (Estimate)

March 20, 2012

Study Record Updates

Last Update Posted (Estimate)

January 13, 2023

Last Update Submitted That Met QC Criteria

January 11, 2023

Last Verified

January 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL36315.042.11
  • 2010-023957-12 (EudraCT Number)

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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