This study has been transitioned to CTIS with ID 2024-517700-12-00 check the CTIS register for the current data. To improve disease-free survival in patients with high-risk rectal cancer by treating these patients with adjuvant chemotherapy in case…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint
The primary endpoint of the study will be disease-free survival in the
intention-to-treat population, calculated from the date of surgery to the date
of recurrence or death from any cause of the patient, whichever occurs first.
The main analysis addressing the primary endpoint will be performed after 118
events, and is planned two years after the last included patient.
Secondary outcome
Secondary endpoints
Secondary outcomes will be disease-free survival, carried out as per protocol
analysis to analyse pure treatment effect. In addition, overall survival will
be calculated measured from the date of surgery to the date of death from any
cause. Quality of life will be assessed in both groups by obtaining
questionnaires already provided by the PLCRC cohort study to compare the effect
of adjuvant chemotherapy on quality of life. The robustness of ctDNA as
biomarker will be analysed by comparing the disease-free survival of patients
with detectable ctDNA who are not treated adjuvant chemotherapy (control group)
with patients with undetectable ctDNA.
Background summary
Rectal cancer is a worldwide cause of cancer related mortality. The incidence
of rectal cancer in the Netherlands is approximately 3500 patients per year.
The introduction of combined neoadjuvant (chemo)radiotherapy and total
mesorectal excision (TME) has significantly reduced the local recurrence rate,
but distant recurrence rates remain around 30%. Recurrences are likely to
derive from residual local disease or subclinical metastatic disease (minimal
residual disease). These micro metastases are undetectable by the currently
used imaging techniques but still present after surgery.
Adjuvant chemotherapy might be beneficial for patients at high risk for
recurrence. However, there are only a few randomised controlled trials on
adjuvant chemotherapy available. Studies on adjuvant chemotherapy in rectal
cancer yielded conflicting results. As a consequence, treatment with adjuvant
chemotherapy in patients with rectal cancer is not evidence based and therefore
not standard of care in the Netherlands. A recent study suggested that
preoperative intensive chemotherapy with radiotherapy, compared to standard
chemotherapy and radiotherapy, resulted in a prolonged disease-free survival.
However, this was at the cost of increased toxicity, and has yet to translate
into an improved overall survival. Consequently, there is an urgent need for
biomarkers to identify those patients at high risk to recur after standard
treatment, to select the patients that might benefit the most from
perioperative chemotherapy. Circulating tumour DNA (ctDNA) in peripheral blood
samples is a potential biomarker to identify patients at high risk for
recurrence. Studies have already demonstrated the strong prognostic value of
detectable ctDNA after surgery in patients with locally advanced rectal cancer,
as it is thought that the presence of ctDNA after surgery is indicative of
minimal residual disease. The REACT study will investigate whether adjuvant
chemotherapy in high-risk rectal cancer patients with postoperative detectable
ctDNA (approximately 15% of the population) improves outcomes.
Study objective
This study has been transitioned to CTIS with ID 2024-517700-12-00 check the CTIS register for the current data.
To improve disease-free survival in patients with high-risk rectal cancer by
treating these patients with adjuvant chemotherapy in case of detectable ctDNA
after surgery.
Our hypothesis is that adjuvant chemotherapy will be beneficial patients with
high-risk rectal cancer and detectable ctDNA after surgery. Patients in this
subgroup have an extremely poor prognosis, with a chance of recurrence
estimated at 70% within two years after surgery. We aim to demonstrate that
adjuvant chemotherapy in these patients will lead to a 25% absolute increase of
the two-year disease-free survival rate compared to follow-up in the control
group (55% vs 30%).
Study design
The proposed study is conducted within the prospective Dutch ColoRectal Cancer
(PLCRC) cohort and follows the trial within cohort (TwiCs) design, i.e. a
randomised controlled trial within a prospective cohort.
Blood samples from rectal cancer patients included in the PLCRC study, meeting
the inclusion criteria and eligible for adjuvant chemotherapy, will be analysed
for the presence of detectable ctDNA. Patients with detectable ctDNA will be
randomised 1:1 according to the TwiCs design to an experimental and a control
group. Patients with undetectable ctDNA will receive treatment and follow-up
according to the current standard of care, and will not receive information
regarding the results of the ctDNA analysis.
Experimental group: Patients with detectable ctDNA and randomised to the
experimental arm will be informed about the test result with associated worse
prognosis and about the study with the possibility to receive adjuvant
chemotherapy. The expected benefits and harms of adjuvant chemotherapy will be
discussed. After thorough counselling, patients will decide whether they are
willing to receive adjuvant chemotherapy consisting of capecitabine and
oxaliplatin (CAPOX) or leucovorin, fluorouracil and oxalilplatin (FOLFOX).
Those willing to receive chemotherapy are asked for informed consent.
Control group: Patients with detectable ctDNA and randomised to the control arm
will not be informed about the test result and will receive routine follow-up.
They had already given informed consent for the possibility of randomisation
in a certain trial within PLCRC with the possibility to serve as a control
patient without being informed as such. Neither the treating physicians will
receive information about the allocation to the control arm and the result of
the ctDNA analysis. Patients in the control arm will not receive experimental
adjuvant chemotherapy (no consequences for this group).
Registration cohort: All patients with undetectable ctDNA will be followed
within PLCRC.
Intervention
Patients with detectable ctDNA after surgery and randomised to the experimental
group will be offered adjuvant chemotherapy within 8 weeks of surgery and no
longer than 12 weeks after surgery. Adjuvant chemotherapy consists of 6 cycles
of 5FU/LV and oxaliplatin (FOLFOX) every 2 weeks or 3-weekly cycles with
capecitabine and oxaliplatin (CAPOX). Duration of treatment will be 3 months
(12 weeks).
Study burden and risks
In current clinical practice there is no indication for adjuvant chemotherapy
for patients after surgery for primary rectal cancer. Therefore all
participating patients have no indication for adjuvant chemotherapy. Patients
randomised to the experimental group will be offered adjuvant chemotherapy to
reduce recurrence. After detailed information and counselling about adjuvant
chemotherapy given by their treating physician, patients will decide whether
they are willing to receive adjuvant chemotherapy. If decided to receive
adjuvant chemotherapy patients will start within 12 weeks after surgery.
According to routine clinical care, patients receiving adjuvant chemotherapy
will undergo blood withdrawals and visit their treating physician before every
cycle of chemotherapy. The combination chemotherapy schedule of CAPOX and
FOLFOX is commonly administered in the adjuvant setting in current practice for
colorectal cancer, therefore the risks and toxicity of the used adjuvant
chemotherapy are well-known. The majority of side-effects are manageable and
transient. Most encountered side-effects of adjuvant chemotherapy are fatigue,
myelosuppression, hand-foot syndrome, nausea, diarrhea, sensory neuropathy,
dysesthesia and rarely cardiac arrhythmias and ischemia. The risk of the
withdrawal of extra tubes of blood during regular blood withdrawal in all study
participants is negligible.
Dr.Molewaterplein 40
Rotterdam 3000CA
NL
Dr.Molewaterplein 40
Rotterdam 3000CA
NL
Listed location countries
Age
Inclusion criteria
• Age >= 18 years
• WHO performance score 0-1
• Informed consent for PLCRC with specific consent for additional blood
withdrawals and offering of future experimental research
• Histological confirmed rectal cancer; either treated with neoadjuvant
(chemo)radiotherapy, and/or clinical T4 and/or N+ in case no neoadjuvant
therapy was administered.
• Eligible to receive treatment with combination adjuvant chemotherapy
(CAPOX/FOLFOX) according to the treating physician
Exclusion criteria
• Another malignancy in previous 5 years, with the exception of treated
carcinoma in situ or skin cancer other than melanoma
• Incomplete primary tumour resection (R1 or R2 resection)
• Contra-indication for fluoropyrimidines or oxaliplatin
• Neoadjuvant oxaliplatin based systemic treatment, e.g. treated with the
RAPIDO regimen consisting of short course radiotherapy followed by 6 cycles of
CAPOX or 9 cycles of FOLFOX prior to surgery
• Patients with a clinical complete response, who will not undergo surgery.
• Pregnant and lactating women
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| EU-CTR | CTIS2024-517700-12-00 |
| EudraCT | EUCTR2022-002580-30-NL |
| CCMO | NL82006.078.22 |