Trial Information

Cytoreductive Surgery Plus Hyperthermic Intraoperative Peritoneal Chemotherapy With Cisplatin to Treat Peritoneal Carcinomatosis From Upper Gastrointestinal Cancer; the HIPCUpp-trial

ASSESSMENT of TUMOUR BURDEN • Tumour burden will be assessed using diagnostic imaging
modalities and verified by surgical or laparoscopic evaluation before CRS+HIPC

- Primary tumour Biliary adenocarcinoma

- Intrahepatic cholangiocellular carcinoma < 3 cm in diameter

- Extrahepatic cholangiocellular carcinoma without invasion of major blood vessels
(portal vein, hepatic arteries, coeliac trunk) Gastric adenocarcinoma Macroscopic
surgical margin of 5 cm is needed to obtain complete tumour removal Pancreatic
adenocarcinoma Tumours located in the head, body or tail of the pancreas without
portal hypertension due to complete encasement of mesenteric/portal vein and
collateral venous circulation

- Liver metastases

- Only liver metastases with stable disease or clinical response to prior systemic
therapy for a period of at least 3 months are eligible

- Not more than 3 metastases, each measuring 3 cm or less in diameter

- Solitary liver metastasis smaller than 5 cm in diameter located in the periphery
of ventral segments (Sg 2-6)

- Peritoneal metastases

- Sugarbaker's peritoneal cancer index (PCI) will be used to assess peritoneal
tumour burden 28. The completeness of cancer resection (CCR) will be assessed by
the surgeon at the end of CRS; CCR-0 no macroscopic residual tumour, CCR-1 no
residual tumour nodules greater than 2.5 mm, CCR-2 residual tumour nodules larger
than 2.5 mm in diameter.

- Patients with PCI < 20 are eligible for this study 11.

THERAPEUTIC INTERVENTION

- CRS is defined as macroscopic tumour removal using surgical resection and/or LAT

o Primary tumour Biliary adenocarcinoma

- Intrahepatic cholangiocellular carcinoma

- Deep parenchymatous tumours are treated by LAT

- Superficial peripheral tumours are treated by resection or LAT

- Distance between tumour and major biliary structures (right, left, main hepatic
duct) needs to be > 1 cm

- Extrahepatic cholangiocellular tumours are treated by surgical resection and
biliodigestive reconstruction

- Distal cholangiocellular tumours with intrapancreatic location are treated by
pancreaticoduodenectomy or LAT at 90°C

- Lymph nodes around the hepatoduodenal ligament are removed Gastric adenocarcinoma

- Partial gastrectomy can be performed either by proximal or distal gastrectomy dependent
on tumour location and size

- Total gastrectomy is performed in patients with signet-ring cell cancers or linitis
plastica

- Tumour-draining lymph nodes are removed Pancreatic adenocarcinoma

- Tumours located in the head of the pancreas and with radiologic or macroscopic vascular
invasion, which need vascular reconstruction at the time of surgery, are treated by LAT
at ablation temperature of 90°C

- Tumours located in the head of the pancreas without radiologic or macroscopic vascular
invasion are treated by pancreaticoduodenectomy or LAT at 90°C

- Tumours located in the body or tail of the pancreas are treated by resection or LAT of
90°C

- Tumour draining lymph nodes are removed

o Liver metastases

- Tumours up to 3 cm are treated by LAT (RFA or MWA)

- Solitary tumour measuring 3 - 5 cm is treated by resection

- Superficial peripheral liver metastases (any diameter up to 5 cm) are allowed to be
resected

o Peritoneal metastases

- Peritonectomy, electrofulguration of superficial (< 3mm depth) metastases, and organ
resection are allowed

- HIPC is administered immediately after CRS: cisplatin at a dose of 100 mg/m2 is
dissolved in 3 litres of normal saline heated to less than 41° Celsius and infused into
the abdominal cavity for a sustained hyperthermic intraperitoneal chemotherapy for 60
minutes. Surgical reconstruction (anastomoses) is performed after HIPC.

TRANSLATIONAL RESEARCH

1. Perioperative quantification of peritoneal and circulating tumour cells

- Real-time qRT-PCR based on detection and quantification of CEA and EpCAM mRNA
transcripts

- Circulating tumour cells in peripheral blood samples will be studied before and at
the end of surgical procedure (CRS+HIPC)

- Peritoneal tumour cells will be evaluated in lavage fluid at the start of surgery
(before any manipulation) and at the end of CRS+HIPC

2. Perioperative systemic cytokine profiles and lymphocyte immunophenotyping

- Plasma concentration of cytokines will be determined using the BDTM Cytometric
Bead Array (CBA): IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, and VEGF

- The relative proportions and absolute numbers B-lymphocytes (CD19+), T-lymphocytes
(CD3+), NK cells (CD56+CD3-), effector T cells (CD3+CD4+ and CD3+CD8+), HLA-DR+ T
cells (CD3+HLA-DR+) and regulatory T cells (CD3+CD4+25+127low) will be quantified
with flow cytometry.

- Time-points for cytokine and immunophenotyping analyses: before surgery (d-1), at
the end of surgery (d0), day after (d1) and at day 7 following CRS+HIPC

3. Gene-expression of primary and metastatic pancreatic cancer

- To better understand cancer biology and search for novel diagnostic and
therapeutic targets, fresh tissue samples from the primary tumour and from
metastases will be stored in RNA-later for RNA-extraction and future analyses.
Hereto, samples obtained from biliary, gastric, and pancreatic cancer tissue will
be stored. Based on the fact that pancreatic cancer is associated with the worst
prognosis, and based on our ongoing research on this disease, gene expression
studies in the current project will be focused on pancreatic cancer.

- In close collaboration with the department of pathology, we have stored
snap-frozen tissue samples from surgically resected human pancreatic cancer for
future research. Clinical, histopathological, and survival data of over 200
patients are registered in our database. Tissue samples (primary and metastases)
from the current study will be analysed together with available 96 primary tumour
samples that have already been controlled to be representative for high quality
RNA studies. These samples are obtained from patients with early and advanced
localized pancreatic cancer in various tumour stages. Gene-expression studies will
be performed using Affymetrix HG U133 Plus 2.0 arrays on primary and metastatic
tissue samples. These experiments will be conducted in close collaboration with
the microarray facility of VIB at KUL.