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

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ClinicalTrials.gov Identifier: NCT01558921
Recruitment Status : Active, not recruiting
First Posted : March 20, 2012
Last Update Posted : January 13, 2023
Sponsor:
Collaborators:
Karolinska University Hospital
Leiden University Medical Center
Uppsala University Hospital
Dutch Cancer Society
Information provided by (Responsible Party):
B. van Etten, MD, PhD, University Medical Center Groningen

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Rectal Cancer Other: M1 scheme Other: standard long course chemoradiotherapy Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 920 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: standard arm: 5.5 weeks chemoradiation -> surgery -> optional chemotherapy experimental arm: 5x5Gy -> 12 wks chemotherapy -> surgery
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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.
Actual Study Start Date : June 21, 2011
Actual Primary Completion Date : March 8, 2020
Estimated Study Completion Date : December 31, 2026
Arms and Interventions
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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.


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.


  2. CRM negative rate [ Time Frame: within 30 days ]
    Circumferential resection margin > 1 mm

  3. pCR rate [ Time Frame: within 30 days ]
    Pathological complete response after neo-adjuvant treatment

  4. Short and long-term toxicity [ Time Frame: 3 year follow-up ]
    Treatment associated toxicity

  5. Surgical complications [ Time Frame: 3 year follow-up ]
    Wound rupture, bleeding, infection, rectal anastomotic leak

  6. Quality of life QLQ-C30 [ Time Frame: 3 year after surgery ]
    Quality of life QLQ-C30

  7. Quality of life QLQ-CR-29+ [ Time Frame: 3 year after surgery ]
    Quality of life QLQ-CR-29+

  8. Quality of life QLQ-CIPN20 [ Time Frame: 3 year after surgery ]
    Quality of life QLQ-CIPN20

  9. Quality of life LARS [ Time Frame: 3 year after surgery ]
    LARS


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01558921


Locations
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Sponsors and Collaborators
University Medical Center Groningen
Karolinska University Hospital
Leiden University Medical Center
Uppsala University Hospital
Dutch Cancer Society
Investigators
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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
  Study Documents (Full-Text)

Documents provided by B. van Etten, MD, PhD, University Medical Center Groningen:
Study Protocol, Statistical Analysis Plan, and Informed Consent Form  [PDF] September 4, 2019

More Information
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Additional Information:

Publications:

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Responsible Party: B. van Etten, MD, PhD, Dr. B. van Etten, surgical oncologist, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT01558921    
Other Study ID Numbers: NL36315.042.11
2010-023957-12 ( EudraCT Number )
First Posted: March 20, 2012    Key Record Dates
Last Update Posted: January 13, 2023
Last Verified: January 2023
Keywords provided by B. van Etten, MD, PhD, University Medical Center Groningen:
rectal cancer
radiotherapy
chemotherapy
5x5
capecitbine
 oxaliplatin
CAPOX
FOLFOX
folinic acid
fluorouracil
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
 Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases