Safety of perioperative hyperthermic intraperitoneal chemotherapy with gemcitabine in patients with resected pancreatic adenocarcinoma: a pilot study of the clinical trial EudraCT 2016-004298-41

Abstract

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) with gemcitabine, after cytoreductive surgery, may reduce the tumor progression of pancreatic cancer through the reduction of the neoplastic volume and the subpopulation of residual pancreatic cancer stem cells, improving the survival of patients with pancreatic cancer and decreasing the recurrence of the disease.

Methods: A pilot study is performed with the first ten patients in the experimental group. A randomized study (phase II-III clinical trial) that requires a population of 42 patients, with 21 patients in each group. All patients have a diagnosis of ductal adenocarcinoma of the pancreas, which will be surgically resected with curative intention. (I) Group I: after an R0 resection, patients receive individualized adjuvant treatments. (II) Group II: after an R0 resection, HIPEC is performed with gemcitabine (120 mg/m² for 30 min), and they also receive individualized adjuvant treatments. To analyze the safety of the procedure, the main variables measured were as follows: grades of complications by means of the Clavien-Dindo system: pancreas surgery complications (e.g., pancreatic fistula, perioperative hemorrhage, delayed gastric emptying, biliary fistula), operative mortality, and laboratory parameters to control system functions. Values were measured three times: preoperatively, twenty-four hours after surgery, and on the 7th postoperative day.

Results: From 2018 to 2019, 31 patients were recruited for our clinical trial. Fifteen patients were excluded because of intraoperative unresectability or a different intraoperative histologic diagnosis. Ten patients were included in the experimental group (resection plus HIPEC gemcitabine). The mean age was 65±7 years, and six patients were female (60%). We confirmed the histologic diagnosis of ductal pancreatic adenocarcinoma in all patients prior to HIPEC. Total pancreatectomy was performed in five patients. The surgical median time was 360 min, and the hospital stay was 11 days. Four patients showed complications classified as Clavien-Dindo type II and one showing type I. Six patients were classified as having stage III tumors. To date, no hospital mortality, locoregional recurrence, or differences between the two groups in terms of perioperative complications, biochemical and gasometric values, or Clavien-Dindo complication grades were observed.

Conclusions: Our clinical pilot study demonstrated a similar perioperative outcome that allows the trial until main objectives are achieved.

Keywords: Pancreatic adenocarcinoma; cancer stem cells (CSCs); chemohyperthermia; gemcitabine; hyperthermic intraperitoneal chemotherapy (HIPEC).

Figure 1

Closed hyperthermic intraperitoneal chemotherapy (HIPEC) technique with CO₂ turbulence. a: Inflow catheter to fill the abdomen with solution; b: outflow catheter to remove the fluids into the HIPEC machine; c: inflow catheter to generate the turbulence with CO₂; d: gas exchanger to control intrabdominal pressure and determine when the abdominal cavity is filled; e: during the recirculation of the drug, the gas exchanger allows the CO₂ to be extracted and the intrabdominal pressure to be controlled.

Figure 2

Patients recruited since 2018 in the clinical trial, and the causes for which some patients were excluded.