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The primary objective of this study is to determine whether the addition of induction chemotherapy to the neoadjuvant treatment of patients with locally recurrent rectal cancer results in more R0 resections compared to treatment with neoadjuvant…
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Ethical review
Approved WMO
Status
Recruiting
Health condition type
Gastrointestinal neoplasms malignant and unspecified
Study type
Interventional
ID
NL-OMON54232
Source
ToetsingOnline
Brief title
PelvEx II
Condition
- Gastrointestinal neoplasms malignant and unspecified
- Gastrointestinal therapeutic procedures
Synonym
Locally recurrent rectal cancer; rectal cancer which returned locally
Research involving
Human
Sponsors and support
Primary sponsor :
Catharina-ziekenhuis
Source(s) of monetary or material Support :
ZonMw
Intervention
Keyword :
Induction Chemotherapy, Locally Recurrent, Neoadjuvant chemoradiotherapy, Rectal Neoplasms, Resection margin
Outcome measures
Primary outcome
To compare the proportion of resections with clear resection margins between
both arms.
Secondary outcome
• To compare the local re-recurrence free survival between both arms.
• To compare the progression free survival between both arms.
• To compare the metastasis free survival between both arms.
• To compare the disease free survival between both arms.
• To compare the overall survival between both arms.
• To determine the pathologic response and compare this between both arms.
• To assess the objective radiological response to the neoadjuvant treatment.
• To determine the toxicity related to the administration of induction
chemotherapy in the experimental arm.
• To determine the compliance to induction chemotherapy in the experimental arm.
• To compare the toxicity related to the administration of chemoradiotherapy
between both arms.
• To compare the compliance to chemoradiotherapy between both arms.
• To compare the number of patients undergoing surgery between both arms.
• To compare surgical characteristics between both arms.
• To compare the rate of major surgical complications between both arms.
• To compare the quality of life between both arms.
• To determine the cost-effectiveness and -utility.
• To systematically collect blood and tissue samples from enrolled patients for
future
Background summary
The most important prognostic factor for survival after surgery in patients
with locally recurrent rectal cancer (LRRC) is a clear resection margin (R0
resection). Unfortunately, achieving an R0 resection in these patients is
challenging because of a distorted anatomy due to prior TME surgery, the
difficult distinction between fibrosis and malignant tissue after previous
radiotherapy and the ingrowth of the recurrent disease in other structures such
as the adjacent organs, pelvic side wall and sacrum. Therefore, all patients
receive neoadjuvant chemoradiotherapy. Despite neoadjuvant treatment with
chemoradiotherapy, R0 resections are achieved in only 60% of patients,
resulting in a 5-year overall survival of only 30%. In addition, incomplete
resections result in 5-year local re-recurrence rates of 70-80% and local
re-recurrence is associated with severe morbidity and a poor quality of life.
A possible way to increase the number of R0 resections, and hereby eventually
decrease the local re-recurrence rate, is the addition of induction
chemotherapy. The addition of induction chemotherapy to the neoadjuvant
treatment of patients with LRRC may lead to more R0 resections by inducing more
local tumour downstaging than what can be achieved with chemoradiotherapy
alone. Worldwide induction chemotherapy in addition to chemoradiotherapy and
surgery for patients with LRRC is increasingly being applied. However, the
additional value of the prolonged and intensified treatment with induction
chemotherapy to chemoradiotherapy and surgery in LRRC is currently not
established. Therefore, there is a strong need for a randomised controlled
trial to determine the value of induction chemotherapy.
Study objective
The primary objective of this study is to determine whether the addition of
induction chemotherapy to the neoadjuvant treatment of patients with locally
recurrent rectal cancer results in more R0 resections compared to treatment
with neoadjuvant chemoradiotherapy alone.
Study design
This is a multicentre, open-label, phase 3, parallel arms, randomised,
controlled study in which eligible patients will be randomised in a 1:1 ratio
between induction chemotherapy followed by neoadjuvant chemoradiotherapy and
surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery
(standard arm).
Intervention
Patients allocated to the experimental arm will receive induction chemotherapy,
consisting of three 3-weekly cycles of CAPOX (capecitabine + oxaliplatin) or
four 2-weekly cycles of FOLFOX (5-fluorouracil + leucovorin +
oxaliplatin)/FOLFIRI (5-fluorouracil + leucovorin + irinotecan). In case of
unacceptable toxicity to capecitabine or 5-fluorouracil, Teysuno
(tagefur/gimeracil/oteracil) may be prescribed, as done in clinical practice.
Hereafter, restaging with thoracoabdominal CT-scan and pelvic MRI will be
performed. In case of irresectable local disease or distant metastases,
palliative treatment will be offered. In case of progressive, but resectable
local disease, patients will start with chemoradiotherapy. In case of stable or
responsive disease, one additional 3-weekly cycle of CAPOX or two additional
2-weekly cycles of FOLFOX/FOLFIRI will be administered. Hereafter, these
patients will also start with chemoradiotherapy. Chemoradiotherapy will be
administered according to standard protocol, in which the dose depends on
whether the patient received prior radiotherapy to the pelvis. Concomitant
chemotherapy agent is capecitabine (or teysuno in case of toxicity) bidaily on
radiotherapy days, according to standard protocol. Four to six weeks after
finishing chemoradiotherapy thoracoabdominal CT-scan and pelvic MRI will be
performed for restaging. In case of irresectable local disease or distant
metastases, palliative treatment will be offered. In case of resectable local
disease, patients will undergo surgery within 10-14 weeks.
Patients allocated to the control arm will receive chemoradiotherapy, according
to standard protocol, followed by surgery within 10-14 weeks.
Study burden and risks
The most important potential risks in the experimental arm are: toxicity of
induction chemotherapy, increased toxicity of chemoradiotherapy and increased
postoperative complications due to a more intensified neoadjuvant treatment.
The chemotherapy agents administered in the experimental arm all have a
marketing authorisation, are used in the authorised form for the authorised
indication, are assessed safe and have well managed side-effects. With regard
to the increased toxicity with chemoradiotherapy and postoperative, several
phase 2 trials in patients with locally advanced rectal cancer showed high
compliance rates to the subsequent chemoradiotherapy as well as acceptable
toxicity and postoperative morbidity.
The extra burden consists of additional visits to the outpatient department
during the administration of induction chemotherapy, one pelvic MRI (40min),
one thoracoabdominal CT-scan (15min, 12.7 mSv), 4 times 3 questionnaires
regarding quality of life and an extra 20ml blood withdrawal during routine
standard of care at 6 or 7 points in time. The extra burden of an additional
20ml blood withdrawal is assessed as negligible, as no additional venepuncture
will be performed. The questionnaires are considered a minimal burden since
they contain brief and intuitive questions and are not very time consuming.
Moreover, patients can separately sign informed consent for these additional
blood withdrawal and questionnaires.
Public
Catharina-ziekenhuis
Michelangelolaan 2
Eindhoven 5623EJ
NL
Scientific
Catharina-ziekenhuis
Michelangelolaan 2
Eindhoven 5623EJ
NL
Listed location countries
Netherlands
Age
Adults (18-64 years)
Elderly (65 years and older)
Inclusion criteria
• 18 years or older
• Confirmed locally recurrent rectal cancer after total or partial mesorectal
resection for rectal cancer or distal sigmoidal cancer either by histopathology
ór clinically proven (evidence on imaging in combination with clinical
findings, with consensus in MDT)
• Resectable disease determined by magnetic resonance imaging (MRI) or deemed
resectable after neoadjuvant treatment with chemoradiotherapy
• WHO performance score 0-1
• Written informed consent
Exclusion criteria
• Radiological evidence of systemic metastatic disease (e.g. liver, lung) at
time of randomisation or in the six months prior to randomisation
• hom*ozygous DPD deficiency (if known in advance)
• Any chemotherapy in the past 6 months
• Any contraindication for the planned chemotherapy chemotherapy (e.g. severe
allergy, pregnancy, kidney dysfunction, thrombocytopenia), as determined by the
medical oncologist
• Radiotherapy in the past 6 months for primary rectal cancer
• Any contraindication for the planned chemoradiotherapy (e.g. severe allergy
to chemotherapy agent, no possibility for radiotherapy due to previous
radiotherapy), as determined by the medical oncologist and/or radiation
oncologist
• Any contraindication for surgery, as determined by the surgeon and/or
anaesthesiologist
• Concurrent malignancies that interfere with the planned study treatment or
the prognosis of resected LRRC.
Design
Study phase :
3
Study type :
Interventional
Intervention model
:
Parallel
Allocation :
Randomized controlled trial
Masking :
Open (masking not used)
Primary purpose :
Treatment
Recruitment
NL
Recruitment status
:
Recruiting
Start date (anticipated) :
Enrollment :
250
Type :
Actual
Medical products/devices used
Product type :
Medicine
Brand name :
5-FU
Generic name :
5-fluorouracil
Registration
:
Yes - NL intended use
Product type :
Medicine
Brand name :
Folinic acid
Generic name :
Leucovorin
Registration
:
Yes - NL intended use
Product type :
Medicine
Brand name :
Irinotecan
Generic name :
Irinotecan
Registration
:
Yes - NL intended use
Product type :
Medicine
Brand name :
Oxaliplatin
Generic name :
Oxaliplatin
Registration
:
Yes - NL intended use
Product type :
Medicine
Brand name :
Xeloda
Generic name :
Capecitabine
Registration
:
Yes - NL intended use
Approved WMO
Date :
Application type :
First submission
Review commission :
MEC-U: Medical Research Ethics Committees United (Nieuwegein)
Approved WMO
Date :
Application type :
First submission
Review commission :
MEC-U: Medical Research Ethics Committees United (Nieuwegein)
Approved WMO
Date :
Application type :
Amendment
Review commission :
MEC-U: Medical Research Ethics Committees United (Nieuwegein)
Approved WMO
Date :
Application type :
Amendment
Review commission :
MEC-U: Medical Research Ethics Committees United (Nieuwegein)
Approved WMO
Date :
Application type :
Amendment
Review commission :
MEC-U: Medical Research Ethics Committees United (Nieuwegein)
Approved WMO
Date :
Application type :
Amendment
Review commission :
MEC-U: Medical Research Ethics Committees United (Nieuwegein)
Approved WMO
Date :
Application type :
Amendment
Review commission :
MEC-U: Medical Research Ethics Committees United (Nieuwegein)
Approved WMO
Date :
Application type :
Amendment
Review commission :
MEC-U: Medical Research Ethics Committees United (Nieuwegein)
Approved WMO
Date :
Application type :
Amendment
Review commission :
MEC-U: Medical Research Ethics Committees United (Nieuwegein)
Approved WMO
Date :
Application type :
Amendment
Review commission :
MEC-U: Medical Research Ethics Committees United (Nieuwegein)
Approved WMO
Date :
Application type :
Amendment
Review commission :
MEC-U: Medical Research Ethics Committees United (Nieuwegein)
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-002141-42-NL |
| ClinicalTrials.gov | NCT04389086 |
| CCMO | NL73593.100.20 |
