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JOURNAL ONKOLOGIE – STUDIE
EPICURE

The Efficacy of PIPAC and Minimally Invasive Radical Resection in High-risk Gastric Cancer Patients.

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NCT-Nummer:
NCT06295094

Studienbeginn:
September 2024

Letztes Update:
06.03.2024

Wirkstoff:
Cisplatin, Doxorubicin

Indikation (Clinical Trials):
Stomach Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Odense University Hospital

Collaborator:
Karolinska University Hospital

Studienleiter

Michael Bau Mortensen, DMSci, PhD
Study Director
University of Southern Denmark (sdu.dk)

Kontakt

Studienlocations
(3 von 5)

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Studien-Informationen

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.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. Peritoneal disease-free survival (Time Frame - 12 months):
Peritoneal disease-free survival (P-DFS) defined as no signs of peritoneal recurrence on (PET) CT and/or control laparoscopy with at least 12 months follow-up after minimally invasive D2-gastrectomy



Secondary outcome:

1. Disease-free survival (Time Frame - 12 months):
Rate of disease-free survival (DFS) with at least 12 months of follow-up

2. Overall survival (Time Frame - 12 months):
Rate of overall survival with at least 12 months of follow-up

3. Length of stay (Time Frame - 30 days):
Length of stay (LOS) (Surgery = Day 0)

4. Postoperative toxicity (Time Frame - 30 days):
Rate of patients with 30 days postoperative toxicity (CTCAE)

5. Postoperative complications (Time Frame - 30 days):
Rate of patients with 30 days postoperative complications (Dindo-Clavien)

6. Postoperative mortality (Time Frame - 90 days):
Rate of patients with 90 days postoperative mortality

7. Rate of positive peritoneal lavage (Time Frame - 90 days):
Rate of positive peritoneal lavage at surgery

8. Patient-reported Quality of life (Time Frame - 30 days & 12 months):
European Organisation for Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)

9. Patient-reported Quality of life (Time Frame - 30 days & 12 months):
European Organisation for Treatment of Cancer Quality of Life Questionnaire Gastric Cancer (EORTC QLC-STO22)

10. Number of patients not receiving adjuvant chemotherapy (Time Frame - 90 days):
Number of patients not receiving adjuvant chemotherapy as planned due to PIPAC related complications.

Studien-Arme

  • Experimental: Pressurized intraperitoneal chemotherapy (PIPAC)
    In the intervention arm, conventional pressurized intraperitoneal chemotherapy (PIPAC) with cisplatin (10.5 mg/m2 body surface in 150ml saline) and doxorubicin (2.1 mg/m2 body surface in 50ml saline) is performed through Medical Device Regulation (MDR) class IIb the CE-certified nebuliser by certified PIPAC surgeons directly after the completion of the minimally invasive gastric resection and reconstruction using the remaining relevant ports. Chemotherapy is administered through a CE-certified nebulizer according to the manufacturer's manual and followed by 30 minutes of simple diffusion. The carbondioxide is evacuated through a closed system, and the abdominal wall is closed according to local surgical standards. The same procedure is repeated, incorporating the same compounds and dose regimens six to eight weeks postoperatively and before the start of the adjuvant part of the perioperative systemic chemotherapy.
  • No Intervention: Standard
    In the control arm, patients will undergo minimally invasive D2 gastrectomy

Geprüfte Regime

  • Cisplatin:
    10.5 mg/m2 body surface in 150ml saline
  • Doxorubicin:
    2.1 mg/m2 body surface in 50ml saline

Quelle: ClinicalTrials.gov


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