Short summary

PIPAC is a new treatment option in patients with peritoneal carcinomatosis. With PIPAC, chemotherapy is administered directly at the target organ (peritoneum), leading to a high tissue concentration of chemotherapy, without systemic uptake and thereby minimizing side effects. This study is a Fase 2 study, where we will evaluate efficacy of PIPAC in a Danish population of patients with peritoneal carcinomatosis.

Rationale

Peritoneal carcinomatosis (PC) represents end stage disease in many types of cancer (e.g. gastric, pancreatic, liver, colo-rectal, ovarian) and, if left untreated, the majority of patients with PC will die from their disease within six months. Platinum-based systemic chemotherapy (SC) may prolong survival in selected patients, but poor performance status and low response rates have led to conservative (nihilistic) treatment strategies in these patients. However, patients with PC who are in good condition and with a remaining life expectancy of more than a few months, may still have an unmet need for additional treatment in order to be able to perform with a high quality of life for as long as possible. These patients have often tried several lines of SC with disappointing results, and alternative and more effective treatment strategies are needed. The installation of chemotherapeutic agents within the peritoneal cavity would seem a simple and effective treatment of PC - at least from a theoretical point of view. Unfortunately, the effect of intraperitoneal chemotherapy on PC is disappointing. Like with SC, the poor response rates may be explained by the poor penetration of the active chemical substances into the PC plaques. Combining cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has gained interest in the recent years, but this approach can only be used in highly selected patients (where CRS is possible), and the procedure carries a significant risk of complications and side effects. Thus, a minimally invasive and safe delivery of relevant chemotherapy in such concentration that may allow it to work efficiently on the PC plaques would be an ideal platform for a new treatment strategy in these patients.

Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC)

Temperature and pressure are important factors during absorption of fluid from the peritoneal cavity, and the use of a relatively low intraperitoneal pressure (2-6 mmHg) seems to increase the inflow of intraperitoneal fluid into the abdominal wall. Studies have confirmed that higher tissue concentrations of chemotherapy may be obtained by increasing the intraperitoneal pressure. After years of extensive testing, and the subsequent development of a CE-certified micro-pump for safe aerosol infusion, a German research group has designed a system that allows laparoscopy guided intraperitoneal aerosol infusion of chemotherapy. The aerosol technique ensures that the entire peritoneal surface is covered by chemotherapy, and this is relevant in patients with PC. With the micro-pump positioned through a standard trocar pointing away from the bowels, a commercially available injection pump provides the necessary pressure to induce an aerosol mist covering the peritoneal cavity. After five minutes, the chemotherapy has been delivered, and the injector is turned off. After an additional 25 minutes of simple diffusion, the intraabdominal air saturated with chemotherapy is evacuated through a standard trocar. At baseline, three series of PIPAC will be planned, and the procedure is repeated every four-six weeks. Recently, the German research group published their experience with PIPAC in gastric, ovarian and colorectal cancer patients with PC, and they documented an overall median survival of 11-16 months after the first PIPAC treatment. These preliminary results suggested a significant efficacy of PIPAC in platinum-resistant PC, and the adverse events profile was very low. This could indicate progress in a palliative situation, where systemic combination chemotherapy is poorly tolerated by the patients.

Based on these results, Professor Michael Bau Mortensen (Odense University Hospital) and Professor Per Pfeiffer (Odense University Hospital) decided to visit the clinical research facilities in Herne (Professor Marc Reymond, Surgical Oncology, Marien Hospital, Universit.tsklinikum der Ruhr-Universitet Bochum, Germany) in order to get more details and in order to learn the technique. During the visit to Herne a formal scientific cooperation between the Department of Surgical Oncology and Therapy Center for Peritoneal Cancer (Marien Hospital, Ruhr-University Bochum) and the Department of Surgery and Department of Oncology (Odense University Hospital) was established. Together with additional experts from different specialties, MBM and PP have formed a PIPAC research group (see below) in order to cover all aspects of PIPAC research and development projects.

PIPAC is not available freely on the market, and the procedure is not EMA/FDA approved yet. The German research team has emphasized, that despite the encouraging results obtained so far, the efficacy and safety of PIPAC still has to be assessed in adequate clinical trials. In March 2015, a feasibility study was initiated at Odense University Hospital (www.clinicaltrial.gov NCT02320448, The Regional Scientific Ethical Committees for Southern Denmark Project-ID: S-20140211), in order to cover the process of implementation and evaluation of this new combined surgical/oncological treatment alternative.

Description of the cohort

Inclusion criteria

• Histological or cytological verified gastrointestinal-, ovarian- or primary peritoneal malignancy (based on tissue from the primary tumor and/or its metastases).
• Ovarian cancer patients must be platinum resistant and have completed at least one line of chemotherapy for platinum resistant disease.
• Radiological, histological or cytological evidence of PC.
• No indication for CRS and HIPEC (according to National Guidelines).
• Performance status 0-1.
• No more than a single extra-peritoneal metastasis.
• Age > 18 years.
• Females must be post-menopausal
• Written informed consent must be obtained according to the local Ethics Committee requirements.

Exclusion criteria

• Symptomatic small bowel obstruction (i.e. total parenteral nutrition, nasogastric tube).
• Previous treatment with maximum cumulative doses of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones.
• A history of allergic reaction to platinum containing compounds or doxorubicin.
• Renal impairment, defined as GFR < 40 ml/min, (Cockcroft-Gault Equation).
• Myocardial insufficiency, defined as NYHA class > 2.
• Impaired liver function defined as bilirubin equal to or above 1.5 x UNL (upper normal limit).
• Inadequate hematological function defined as ANC equal to or below 1.5 x 109/l and platelets equal to or below 100 x109/l.

Data and biological material

• Demographic data
• Perioperative data
• Peritoneal biopsies
• Peritoneal lavage fluid
• Baseline and follow-up MRI of the abdomen
• Blood tests for Prognostic Nutritional Index (PNI)
• EORTC QLQC-30 (QoL)

Collaborating researchers and departments

Department of Surgery, Odense University

• PhD-student Martin Graversen, MD
• Professor Michael Bau Mortensen, MD, DMSc, PhD
• Consultant Claus Fristrup, MD, PhD

Department of Oncology, Odense University Hospital

• Professor Per Pfeiffer, MD, PhD
• Professor Jørn Herrstedt, MD, DMSc
• Senior registrar, Jon Kroll Bjerregaard, MD, PhD

Department of Clinical Pathology, Odense University

• Consultant Sönke Detlefsen, MD, PhD
  

• Monitor Stella Nielsen