This is a prospective, open label, randomized multicenter phase III clinical study that
aims to evaluate the effects of PIPAC combined with systemic chemotherapy vs. intravenous
systemic chemotherapy alone on patients with gastric cancer and synchronous positive
peritoneal cytology and/or limited peritoneal metastasis (PCI ≤ 6). Patients will be
randomly assigned in a 1:1 ratio to Arm A: intravenous chemotherapy (FOLFOX) vs. Arm B:
intravenous chemotherapy (FOLFOX) plus PIPAC with cisplatin and doxorubicin.
Patients eligible for the trial must have performed: diagnostic upper intestinal
endoscopy with biopsies, thoraco-abdominal-pelvic CT scan, laboratory exams: serum CEA,
CA19.9, hemoglobin, leukocytes, neutrophils, platelets, glycemia, AST, ALT, LDH, total
bilirubin, alkaline phosphatase, serum albumin, total protein, plasmatic APTT, PT,
creatinine clearance and serum creatinine and pregnancy serological test.
Patients should undergo to staging laparoscopy in one of the participating centers to
define the peritoneal involvement. After that peritoneal metastasis will be confirmed by
cytological/histopathological final examination and after receiving the written informed
consent, patient will be randomized.
Once the inclusion and exclusion criteria are confirmed, each patient will be randomized
in a 1:1 ratio (Chemotherapy alone vs chemotherapy plus PIPAC) to blocks of 14 using a
centralized randomization list, stratified by center. Randomization list will be managed
by the Medical Epidemiology and Statistics Unit, Department of Diagnostics and Public
Health of the University of Verona. This list will be built using the Biostatistics Unit
of the University of Verona using software (www.randomizer.org) Patients randomized in
the Arm A will undergo to 6 courses of systemic chemotherapy according to FOLFOX regimen,
after these six courses of chemotherapy, radiologic restaging (CT scan) as well as a
second staging laparoscopy will be performed. If a Progression Disease will be detected,
the patient will end the trial and will undergo to II line chemotherapy regimen. If a
stable disease or a partial response will be documented, after a multidisciplinary
discussion, patient will undergo to either further 6 courses of chemotherapy or to
cytoreductive surgery plus HIPEC.
Patients randomized in the ARM B will undergo to 6 courses of systemic chemotherapy
(FOLFOX regimen) plus PIPAC every two cycles of chemo. At least seven days should last
between each PIPAC and the next chemotherapy course, and at least 14 days should last
between the chemotherapy course and the next PIPAC. After six courses of chemotherapy and
3 PIPACs procedure, a radiologic restaging (CT scan) as well as a laparoscopic
reassessment will be performed. If a Progression Disease will be detected, the patient
will end the trial and will undergo to II line chemotherapy regimen. If a stable disease
or a partial response will be documented, patient will be treated with cytoreductive
surgery plus HIPEC.
A minilaparotomy of 3 cm is performed, usually in the midline. Then, a 5 or a 10-12 mm
balloon trocar is inserted under "finger protection" usually in the right side and the
fascia of the minilaparotomy, is then closed. The abdomen is insufflated with CO2 and
tightness is controlled with saline solution in the minilaparotomy. CO2-bubbling
documents incomplete closure. A second 10-12mm trocar is then introduced safely under
videoscope control usually in upper left side. Ascites volume is documented, and ascites
is removed sending a sample for cytological examination, an accurate exploratory
laparoscopy is performed, possibly placing an additional 5 or 10-12 mmHg trocar in an
area not affected by adhesions or disease, the Peritoneal Cancer Index is calculated.
Multiple biopsies are performed in different abdominal quadrants during the first
procedure and all following procedures to ascertain tumor regression grade. Then, a
nebulizer CAPNOPEN© is connected to an intravenous high-pressure injector and inserted
into the upper left side trocar and fixed with a 45° angle to the underlying peritoneum
to allow a better spatial drug distribution pattern and a greater spraying distance
between the nozzle head and the underlying small bowel peritoneum compared to the that
obtained with a perpendicular nozzle position.
The liquid chemotherapeutic drugs (Cisplatin 10.5 mg/m2 body surface in a total of 150 mL
NaCl 0.9 %; Doxorubicin 2.1 mg/m2 body surface in a total of 50 mL NaCl 0.9 %) are then
injected through remote control with a flow rate of 0.7 mL/sec with a maximum operating
pressure of 200 psi (13 bar) into the constant capnoperitoneum of 12 mm Hg. After an
aerosol exposure phase of 30min, the aerosol is evacuated via a closed aerosol waste
system. Finally, trocars are retracted, and laparoscopy ended. No drainage of the abdomen
is applied.
FOLFOX regimen systemic chemotherapy will be administered to each patient in both arms.
Arm A will receive only systemic chemotherapy according to this scheme: Oxaliplatin 85
mg/m2, d1, over 2 h, Leucovorin 400 mg/m2, d1 i.v. over 2 h, 5-FU 400 mg/m2 in bolus and
5-FU 2.400mg/m2, d1, i.v. over 46 h. Arm B will be treated with systemic chemotherapy
plus PIPAC procedure according to this scheme (Fig.1): PIPAC with Cisplatin 10,5 mg/m2
and Doxorubicin 2,1 mg/m2; chemotherapy with the same way of Arm A. At least seven days
should last between each PIPAC and the next chemotherapy cycle, and at least 14 days
should last between the chemotherapy cycle and the following PIPAC procedure.
Secondary Resectability Rate (%) evaluated as the rate of patients of the two arms that
get radical intent surgery (cytoreductive surgery and HIPEC).
According to the current literature, considering a resectability rate of 50%9 for
patients undergoing chemotherapy alone (arm A) and 80% in the experimental arm (arm B),
the investigators need 88 patients (44 per group) to achieve 80% potency by performing an
exact bidirectional Fisher test with an alpha of 5%.
Expecting a dropout rate of 10% it will be necessary to recruit 98 patients, 49 for each
arm. A very similar recruitment capacity is envisaged in the different centers.
The enrollment of patients will last about three and a half years from the date of
approval. An enrollment of about 30 patients per year is expected in the 7 centers
involved. If the enrollment is lower than expected, up to 10 centers will be recruited
and the enrollment period will be extended. These latter changes will be the subject of
any future substantial amendment to the current study protocol.
Patients will be involved in the study from the time of enrollment, the duration of
treatment (from a minimum of 3 months to a maximum of 6 months) and for the next 3 years
of follow-up.
The clinical trial will last a total of six and a half years. The end of data collection
coincides with the achievement of a three-year follow-up for the last patient enrolled.
An additional year will be needed for the analysis of the data and the publication of the
results.