Primary objectiveTo investigate whether the addition of preoperative radiochemotherapy to the standard treatment, consisting of explorative laparotomy, pancraticoduodenectomy if possible, followed by adjuvant chemotherapy, improves the overall…
ID
Source
Brief title
Condition
- Exocrine pancreas conditions
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint
Overall survival is defined as the period of time between randomization and
death from any cause. Patients alive at last follow-up are censored.
Secondary outcome
Secondary endpoints that will be compared between the randomization arms are
defined as follows:
- Resection rate is defined as the percentage of eligible randomized patients
that actually underwent a resection. Patients that do not undergo an
explorative laparotomy at all or do undergo an explorative laparotomy but not a
resection are considered a failure.
- R0 resection rate is defined as the percentage of eligible randomized
patients that underwent a microscopically complete (or R0) resection. The
resection is considered R0 if the inked margin is further than 1 mm distinct
from any tumour cells.
- Disease free survival is defined as survival without overt recurrent
pancreatic cancer from the date of randomization, as discovered following
complaints of the patient or on routine CT-scan at 6 months intervals. Any sign
of recurrent or persistent disease, locoregional or distant, as well as death
from any cause is considered an event for this endpoint. Patients that do not
undergo an explorative laparotomy at all or do undergo an explorative
laparotomy but not a resection are considered a failure at time point zero.
- Time to locoregional failure is defined as the period of time without
locoregional recurrence after randomisation. Locoregional recurrence is
considered an event and patients are censored at death or distant metastases
without locoregional recurrence. Patients that do not undergo an explorative
laparotomy at all or do undergo an explorative laparotomy but not a resection
are considered a failure at time point zero.
- Time to distant metastases is defined as the period of time without distant
metastases after randomisation. Distant metastases are considered an event and
patients are censored at death.
- Postoperative complications are defined according to the
internationally-accepted Clavien-Dindo classification and definitions of
post-pancreatic surgery complications (pancreatic fistula, delayed gastric
emptying, bleeding) by the International Study Group on Pancreatic Surgery
(analysis on intent-to-treat and per-protocol in patients undergoing
PD/Whipple).
Background summary
Pancreatic cancer has a dismal prognosis. Pancreaticoduodenectomy may offer
cure but only a small percentage of patients can undergo a resection, and also
in this cohort the survival is poor. Adjuvant chemotherapy offers a modest
survival benefit. Based on multiple single-arm phase 2 studies and a SEER
database observational study, it is suggested that preoperative
radiochemotherapy may offer a survival benefit for patients with borderline
resectable and resectable pancreatic cancer by increasing the resection rate
and the R0 resection rate. The interpretation of these data is hampered by the
lack of a control arm and the inherent selection bias of phase 2 studies (for
example by only reporting on the subset of patients in whom a R0 resection is
achieved). The only way to evaluate the role of preoperative radiochemotherapy
concerning resection rate, R0 resection rate and subsequent overall survival is
to perform a prospective randomized study with intent-to-treat analysis. To
evaluate the benefit of preoperative radiochemotherapy the Dutch Pancreatic
Cancer Group (DPCG) initiates a prospective randomized phase 3 study: PREOPANC.
In this study, patients with borderline resectable and resectable pancreatic
cancer are randomized between surgery followed by 6 months adjuvant
chemotherapy with gemcitabine (the current standard), and neoadjuvant
chemotherapy with 3 months gemcitabine to which radiotherapy is added in the
2nd month, followed by surgery and adjuvant chemotherapy with 4 months of
gemcitabine (experimental arm). The feasibility of this schedule has been
demonstrated in previous phase II studies. Resectability or borderline
resectability will be assessed according to well-defined criteria. In the
experimental arm, biliary drainage and laparoscopy will be performed before the
start of radiochemotherapy. A total of 244 patients (176 events) are required
to demonstrate a difference of 6 months (from 11 to 17 months) in median
overall survival by intent-to-treat.
Study objective
Primary objective
To investigate whether the addition of preoperative radiochemotherapy to the
standard treatment, consisting of explorative laparotomy,
pancraticoduodenectomy if possible, followed by adjuvant chemotherapy, improves
the overall survival (analyzed by intent to treat) of patients with resectable
or borderline resectable pancreatic cancer.
Study design
Study design
This study is a multicenter, randomized, parallel superiority phase III
clinical trial. Patients will be randomized between standard treatment or
standard treatment preceded by laparoscopy and radiochemotherapy. Primary
outcome will be all-cause survival after randomization. All patients will be
followed until death or at least 24 months after inclusion.
The survival data will be used for the evaluation of the survival difference
between the two randomization groups. Randomization will be stratified for
participating institution. Furthermore patients will be stratified to
resectability/borderline resectability.
Intervention
Laparoscopy
In the radiochemotherapy arm, a laparoscopy will be planned so that the start
of radiochemotherapy will not be later than 4 weeks after randomization.
Laparoscopy is performed according to institutional guidelines. The minimum
requirements of a successful procedure are: visualisation of the peritoneum,
liver surface, diaphragm and base of the large bowel mesenterium. No peritoneal
washings are performed. .
Chemoradiotherapy
In patients randomized to radiochemotherapy, if laparoscopy has not revealed
peritoneal or liver metastases, radiotherapy to the pancreatic tumour with a
margin for position variation and movement of the pancreas and tumour will be
planned. A hypofractionated scheme of 15 fractions of 2.4 Gy in three weeks
will be applied, combined with the second course of gemcitabine (gemcitabine
1000 mg/m2, day 1,8,15).
Study burden and risks
Side effects of the chemoradiation therapy as described in the protocol and in
the patient information
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
1. Histologically or cytologically confirmed adenocarcinoma of the pancreas;2. Primarilly resectable tumours or Borderline resectable tumours ;3. Karnofsky performance status >= 70%;4. Ability to undergo surgery and radiochemotherapy;5. Leucocytes >= 3.5 X 10.9/l;6. Platelets >= 100X 10.9/l;7. Hemoglobin >= 6 mmol/l;8. renal function: E-GFR > 50 ml/min;9. Age >= 18 jaar;10.Written informed concent;11. Patients with reproductive potential must use effective contraception
Exclusion criteria
1.T1 resectable tumours, centrally located with no connection to the SMA, Celiac axis, CHA or SMV/PV;2. Clearly locally advanced, irresectable, tumours ;3. Carcinoma of the Papilla Vateri;4. Co morbidity precluding surgery or radiochemotherapy;5. Distant metastases, including cytologically proven N2 lymph node metastases (base of the celiac trunk or between inferior vena cava and aorta);6. Previous radiotherapy or chemotherapy precluding radiochemotherapy;7. Previous active malignancy shorter than 5 years before diagnosis of pancreatic cancer;8. Pregnancy;9. Imminent bowel obstruction;10. Active bleeding;11 Uncontrolled infection;12. Anamnestically known positive status for HIV or hepatitis B or C
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 |
|---|---|
| EudraCT | EUCTR2012-003181-40-NL |
| CCMO | NL40472.078.12 |