This study has been transitioned to CTIS with ID 2024-516260-29-00 check the CTIS register for the current data. To determine whether neoadjuvant FOLFIRINOX followed by surgery improves overall survival and quality of life compared to neoadjuvant…
ID
Source
Brief title
Condition
- Exocrine pancreas conditions
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main endpoint is overall survival (OS).
Secondary outcome
• Chemotherapy rate, defined as the percentage of eligible randomized patients
who received at least one cycle of chemotherapy.
• Chemotherapy completion rate, defined as the percentage of eligible
randomized patients who completed all cycles of scheduled chemotherapy.
• Staging laparoscopy rate, defined as the percentage of eligible randomized
patients that actually underwent a staging laparoscopy, regardless whether a
laparotomy or resection was performed.
• Laparoscopy yield, defined as the percentage of patients that underwent
staging laparoscopy and were diagnosed with metastatic disease during this
procedure.
• Exploratory laparotomy rate, defined as the percentage of eligible randomized
patients who actually underwent an exploratory laparotomy, regardless whether a
resection was performed.
• Resection rate, defined as the percentage of eligible randomized patients
that underwent a curative-intent resection.
• R0 resection rate, defined as the percentage of eligible randomized patients
that underwent a microscopically complete (R0) resection. The resection is
considered R0 if the inked margin is more than 1 mm away from tumor cells.
• Progression-free survival, defined as survival without progressive or
recurrent pancreatic cancer from the date of randomization. Death from any
cause is also considered an event for this endpoint.
• Locoregional recurrence free interval (LRFI), defined as the period of time
without locoregional recurrence after randomization. A locoregional failure is
any persistent or recurrent pancreatic cancer in the original tumor location,
or the N1 lymph node areas.
• Distant metastases free interval (DMFI), defined as the period of time
without distant metastases after randomization.
• Disease free survival (DFS), defined as the period of time between
randomization and locoregional recurrence, occurrence of distant metastases or
second pancreatic cancer, or death (all causes).
• Locoregional recurrence free interval (LRFI), defined as the time interval
between the day of randomization and the date of locoregional recurrence,
including the N1 lymph node areas.
• Postoperative complications, defined according to the Clavien-Dindo
classification and definitions of post-pancreatic surgery complications
(pancreatic fistula, delayed gastric emptying, and bleeding) by the
International Study Group on Pancreatic Surgery.
• Toxicity, gastro-intestinal and hematologic, according to CTCAE version
4.0.3, until 90 days after the last dose of chemotherapy.
• Quality of life years (QALYs) from randomization until last follow-up.
• Indirect and direct medical and nonmedical costs.
• Incremental cost-effectiveness ratio (ICER). Is calculated as the ratio
between the difference in QALYs and the difference in total costs per patient.
• Predictive value of biomarkers in serum and resected tumors.
• Clinical response rate defined according to RECIST criteria version 1.1
comparing pre-randomization and restaging imaging after preoperative
chemoradiotherapy and after 4 and 8 cycles of FOLFIRINOX.
• Serum Cancer Antigen 19-9 (CA 19.9) and Carcino-Embryonal-Antigen (CEA)
response, defined as the change in CA 19-9 and CEA after preoperative
chemoradiotherapy and after 4 and 8 cycles of FOLFIRINOX compared to baseline.
• Pathologic response, 3-tier histologic tumor regression grading (HTRG)
scheme; HTRG 0, no viable tumor; HTRG 1, <5% viable tumor cells; HTRG 2, >=5%
viable tumor cells.
Background summary
The annual incidence of pancreatic cancer in the Netherlands is approximately
3500 patients. In 2030, pancreatic cancer is expected to be the second leading
cause of cancer death. The 1-year overall survival (OS) for pancreatic cancer
in the Netherlands is 20%; the 5-year OS is only 3%.
Upfront resection with adjuvant gemcitabine has been the standard of care for
patients with (borderline) resectable pancreatic cancer in the Netherlands as
stated in the Dutch national guideline. However, the recent Dutch multicenter
PREOPANC-1 trial, found that neoadjuvant gemcitabine based chemoradiotherapy
followed by resection and adjuvant gemcitabine confers superior overall
survival (median 17 vs 13 months, p<0.05). These results confirm the results of
a systematic review and a smaller Korean trial. Since FOLFIRINOX (a combination
of 5-fluorouracil, irinotecan, oxaliplatin, and leucovorin) is more potent
chemotherapy compared to gemcitabine, this treatment may further improve
survival. Moreover, it is already the standard of care in patients with locally
advanced and metastatic pancreatic cancer. A patient-level meta-analysis of
FOLFIRINOX for patients with (borderline) resectable pancreatic cancer found a
median overall survival of 24 months.
Study objective
This study has been transitioned to CTIS with ID 2024-516260-29-00 check the CTIS register for the current data.
To determine whether neoadjuvant FOLFIRINOX followed by surgery improves
overall survival and quality of life compared to neoadjuvant chemoradiotherapy
followed by surgery and adjuvant gemcitabine in patients with (borderline)
resectable pancreatic cancer in an intention-to-treat setting.
Study design
Prospective multicenter randomized phase III clinical superiority trial.
Intervention
8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery.
Study burden and risks
All patients (standard of care)
Patients will undergo a triphasic CT scan of the chest and abdomen to rule out
metastatic disease and determine resectability. Endoscopic Ultrasonography with
Fine Needle Aspiration (EUS/FNA) is performed to obtain a pathological
diagnosis. Patients with hyperbilirubinemia may be randomized, but biliary
drainage should be performed before start of neoadjuvant therapy if bilirubin
is higher than 1.5 times upper limit of normal.
After treatment, patients will go into routine follow-up for 5 years. Follow up
includes regular outpatient clinic visits, CT scans when indicated, and blood
collection. All patients are asked to complete questionnaires during follow-up.
Patients in the intervention arm
The treatment starts with 4 cycles of chemotherapy with FOLFIRINOX. If a CT
scan shows no disease progression after 4 cycles, the patient will receive an
additional 4 cycles of chemotherapy. If a CT scan shows (borderline) resectable
disease after chemotherapy, the patient will undergo curative-intent surgery.
Surgery will start with a staging laparoscopy (i.e. in the same operation) to
rule out occult metastatic disease. A resection is performed in the absence of
metastatic or locally advanced (i.e. unresectable) disease. No adjuvant
chemotherapy is given. Patients with metastatic or locally advanced disease at
restaging or surgery continue with palliative treatment or receive best
supportive care; these patients forgo a resection. Patients who discontinue
chemotherapy because of toxicity proceed to surgery without completing all
scheduled cycles of chemotherapy.
Toxicity of the FOLFIRINOX regimen is well described, because it is the
standard of care in the metastatic and locally advanced setting. Severe
toxicity is more common with FOLFIRINOX than with gemcitabine. However, in two
large studies no death was attributed to FOLFIRINOX.
Patients in the comparator arm
Treatment in the standard arm starts with a schedule based on three cycles of
full-dose gemcitabine, adding hypofractionated radiotherapy (36 Gy in 15
fractions) during the second cycle. This chemoradiotherapy is followed by
surgery within 4-6 weeks after completion of chemotherapy, followed within 12
weeks by 4 cycles of adjuvant gemcitabine.
Dr. Molewaterplein 40 230
Rotterdam 3015 GD
NL
Dr. Molewaterplein 40 230
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
• Histologically or cytologically confirmed pancreatic cancer (i.e. pancreatic
ductal adenocarcinoma)
• (Borderline) resectable tumor without metastatic disease
• WHO performance status 0 or 1
• Ability to undergo surgery, chemoradiotherapy and chemotherapy
• Leucocytes (WBC) >= 3.0 X 109/l (should be assesed within 4 weeks prior to
randomization)
• Platelets >= 100X 109 /l (should be assesed within 4 weeks prior to
randomization)
• Hemoglobin >= 6 mmol/l (should be assesed within 4 weeks prior to
randomization)
• Renal function: E-GFR >= 50 ml/min (should be assesed within 4 weeks prior to
randomization)
• Age >= 18 years
• Written informed consent
Exclusion criteria
• Prior radiotherapy, chemotherapy, or resection for pancreatic cancer.
• Prior radiotherapy or chemotherapy precluding chemoradiotherapy or FOLFIRINOX.
• Previous malignancy (excluding non-melanoma skin cancer, pancreatic
neuroendocrine tumor (pNET) <2cm, and gastrointestinal stromal tumor (GIST)
<2cm), unless no evidence of disease and diagnosed more than 3 years before
diagnosis of pancreatic cancer, or with a life expectancy of more than 5 years
from date of inclusion.
• Pregnancy.
• Serious concomitant systemic disorders that would compromise the safety of
the patient or his/her ability to complete the study, at the discretion of the
investigator.
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
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-516260-29-00 |
| EudraCT | EUCTR2017-002036-17-NL |
| CCMO | NL61961.078.17 |