Trial Title:
The Efficacy of PIPAC and Minimally Invasive Radical Resection in High-risk Gastric Cancer Patients.
NCT ID:
NCT06295094
Condition:
Gastric Cancer
Chemotherapy, Adjuvant
Peritoneal Metastases
Minimally Invasive Surgical Procedures
Conditions: Official terms:
Stomach Neoplasms
Doxorubicin
Conditions: Keywords:
PIPAC
Gastric cancer
Minimally invasive gastrectomy
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Prevention
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Cisplatin
Description:
10.5 mg/m2 body surface in 150ml saline
Arm group label:
Pressurized intraperitoneal chemotherapy (PIPAC)
Intervention type:
Drug
Intervention name:
Doxorubicin
Description:
2.1 mg/m2 body surface in 50ml saline
Arm group label:
Pressurized intraperitoneal chemotherapy (PIPAC)
Summary:
The goal of this randomized clinical trial is to investigate whether pressurized
intraperitoneal chemotherapy (PIPAC), delivered immediately after minimally invasive D2
gastrectomy and repeated 6-8 weeks later, improves 12-month peritoneal disease-free
survival in patients with high-risk gastric adenocarcinoma when compared to standard
treatment.
Detailed description:
Despite declining incidence, gastric adenocarcinoma (GAC) is considered the fifth most
common cancer worldwide and the third leading cause of cancer death globally. Its
incidence varies across different parts of the globe, with a low incidence in the West.
In East Asia, especially Japan and Korea, the incidence of distal GAC remains high,
whereas proximal GAC tends to dominate in the West. Gastroesophageal junction (GEJ)
adenocarcinomas that have the epicentre in the proximal 2 to 5 cm of the stomach (Siewert
type III) should be staged and treated as GAC.
The consensus in most Western countries is that medically fit GAC patients should undergo
D2 gastrectomy, carried out in specialised, high-volume centres with perioperative
outcomes in terms of morbidity and mortality rates comparable to those presented in Japan
and South Korea. A minimally invasive D2 gastrectomy has emerged as a valid and
preferable alternative to open surgery.
Despite significant progress in implementing preventive strategies and curative treatment
of premalignant and early neoplastic gastric lesions, most GAC patients still present
with advanced stages of the disease, leading to a dismal prognosis even after treatments
with curative intent. Given that many patients relapse following surgery, various
multimodal treatment strategies have been studied to improve survival rates, mainly by
combining surgery with systemic treatment in the form of perioperative chemotherapy.
Clinical research has explored and documented the concept of perioperative chemotherapy
in GAC and cancers originating in the distal esophagus and GEJ. Noteworthy is that some
of these have suggested that the tumours with the most obvious responses to corresponding
regimens originate in the esophagus and GEJ. Moreover, GACs of poorly differentiated
tubular type or poorly cohesive cancer, regardless the presence of signet-ring cells type
has been reported to be more resistant to chemotherapy regimens. Another observation with
clinical implications is that GAC patients with malignant cells retrieved from peritoneal
lavage before surgery have an extremely poor prognosis. Hence, laparoscopy with
peritoneal lavage for malignant cells is recommended in all stage IB-III gastric cancers,
otherwise considered potentially resectable, to exclude radiologically occult metastatic
disease. The true value of this information may be even greater for patients with T3/T4
disease. Considering the above-mentioned challenges, it is critically important to
explore novel multimodal therapeutic concepts in GAC since current therapeutic strategies
offer these patients a limited option for cure.
The occurrence of peritoneal metastases (PM) has a significant negative impact on the
overall prognosis, with a median survival of three to four months without treatment. None
of the available chemotherapy regimens has reduced or prevented the risk of PM. It is
commonly believed that PM occur through the deposition of tumour cells either by the
direct extension and subsequent cellular exfoliation or through the traumatic
dissemination of cancer cells during surgery. Clinical validation of the concept of
direct spread is also provided by observing the higher rate of PM seen with increasing
tumour stages (T-stages) and serosal involvement. This is also supported by the
association of between positive peritoneal cytology and a higher tumour stage.
Sixty percent of lavage cytology-negative patients will convert to a cytology-positive
state immediately after gastrectomy. Accordingly, it can be argued that during
gastrectomy, cancer cells within the dissected lymphatic channels and blood vessels are
released to and disseminated throughout the abdominal cavity. Free cancer cells can then
attach to the peritoneal surface, a process facilitated by the action of cytokines and
the deposition of fibrin layers, allowing for the entrapment of those cells. This new
restrictive-peritoneal environment is thought to hinder the penetrance of cytotoxic drugs
delivered systemically and provides grounds for the launch of intraperitoneal treatments.
Based on the minimal effects of traditional regimens on GAC, exploring alternative
perioperative therapeutic concepts appears of the highest clinical significance. Since
only a fraction of the systemically administered chemotherapy reaches the peritoneum, the
effect of intraperitoneal chemotherapy has been extensively studied. A new aerosol
technique, Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC), improves
intraperitoneal delivery and subsequent uptake of chemotherapy. It has shown promising
results in patients with PM from colorectal, ovarian, pancreatic, and gastric cancer.
Furthermore, PIPAC is feasible, safe, and well tolerated by many patients when
administered in the palliative setting.
Randomised studies on prophylactic treatment of high-risk GAC patients (serosal invasion)
using intraperitoneal chemotherapy or hyperthermic intraperitoneal chemotherapy (HIPEC)
are mainly from Asian institutions. The risk of postoperative morbidity and mortality did
not seem to be negatively influenced by intraoperative, intraperitoneal chemotherapy,
contrasting to western non-randomized trials reporting considerable morbidity and
mortality after these combined procedures. Thus, the use of prophylactic HIPEC in
non-metastatic high-risk GAC is still debated.
Data from Odense PIPAC Centre on the outcome of PIPAC with low-dose cisplatin and
doxorubicin in GAC patients with chemotherapy-resistant PM revealed objective tumour
response in 40% of the patients after three PIPAC directed therapies. An additional 20%
had no further tumour progression. These observations in GAC patients deliver further
evidence suggesting that PIPAC can induce regression of resistant PMs in several cancer
types and carries the potential to meet the clinical need for new and better therapies.
Our results also provide evidence that low-dose PIPAC therapy might effectively treat
patients with recurrent, chemo-resistant gastric PMs, including the poorly differentiated
tubular type or poorly cohesive cancer.
The pivotal question is whether PIPAC delivered immediately after a laparoscopic D2
gastrectomy for GAC can reduce the risk of recurrent PM. Our institutions' recent phase I
trial has shown this therapeutic concept to be feasible and safe. Hence, a randomised
phase-II clinical trial must be conducted to assess the impact of PIPAC on disease-free
survival in patients with high-risk GAC who are offered surgical treatment with curative
intent.
Criteria for eligibility:
Criteria:
Inclusion criteria
- Gastric or Gastroesophageal junction Siewert type III adenocarcinomas
- Clinical T3-4a-stages
1. Any differentiation grade
2. Any histological subtype
- Clinical T2-stage
a. If poorly differentiated or of the poorly cohesive histological subtype, with or
without the presence of signet-ring cells
- Any clinical T-stage with positivity for malignant cells on abdominal lavage
cytology, which is converted to cytology negative in response to neoadjuvant
chemotherapy.
- Any clinical nodal-stage
- clinical M0-stage (positive abdominal wash cytology, which is converted to cytology
negative in response to neoadjuvant therapy, is permitted)
- Performance status Eastern Cooperative Oncology Group (ECOG) 0-1
- Age 18 - 80 years
- Undergoing robotic or laparoscopic D2 gastrectomy
- Able and willing to provide written informed consent and to comply with the clinical
study protocol
- Fertile women must have a negative pregnancy test at the time of inclusion and must
use adequate contraception.
Exclusion criteria
- Previous allergic reaction to cisplatin, doxorubicin or other platinum-containing
compounds.
- Renal impairment, defined as glomerular filtration rate (GFR) < 40 ml/min
(Cockcroft-Gault Equation).
- Myocardial insufficiency, defined as New York Heart Association (NYHA) class 3-4.
- An impaired liver function, defined as bilirubin ≥ 1.5 x upper normal limit (UNL).
- An inadequate haematological function, defined as absolute neutrophil count (ANC)
<1.5 x 109/l and platelets <100 x 109/l.
- Any other condition or therapy which, in the investigator's opinion, may pose a risk
to the patient or interfere with the study objectives.
Gender:
All
Minimum age:
18 Years
Maximum age:
80 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
City of Hope
Address:
City:
Duarte
Zip:
91010
Country:
United States
Contact:
Last name:
Yanghee Woo, PhD
Email:
yhwoo@coh.org
Facility:
Name:
Odense University Hospital
Address:
City:
Odense C
Zip:
5000
Country:
Denmark
Facility:
Name:
University Hospital Lille
Address:
City:
Lille
Country:
France
Contact:
Last name:
Clarisse Eveno, PhD
Email:
clarisse.eveno@gmail.com
Facility:
Name:
Charité, University of Berlin
Address:
City:
Berlin
Country:
Germany
Contact:
Last name:
Beate Rau, PhD
Email:
beate.rau@charite.de
Facility:
Name:
Karolinska University Hospital
Address:
City:
Stockholm
Country:
Sweden
Start date:
September 2024
Completion date:
January 2028
Lead sponsor:
Agency:
Odense University Hospital
Agency class:
Other
Collaborator:
Agency:
Karolinska University Hospital
Agency class:
Other
Source:
Odense University Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06295094
