A Prospective, Phase I/II, Open-Label Pilot Trial to Assess the Safety of Hyperthermic Intraperitoneal Chemotherapy After Oncological Resection of Pancreatic Adenocarcinoma

Can Yurttas, Philipp Horvath, Imma Fischer, Christoph Meisner, Silvio Nadalin, Ingmar Königsrainer, Alfred Königsrainer, Stefan Beckert, Markus W Löffler, Can Yurttas, Philipp Horvath, Imma Fischer, Christoph Meisner, Silvio Nadalin, Ingmar Königsrainer, Alfred Königsrainer, Stefan Beckert, Markus W Löffler

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a common fatal disease with unfavorable prognosis, even after oncological resection. To improve survival, adding hyperthermic intraperitoneal chemotherapy (HIPEC) has been suggested. Whether HIPEC entails disproportional short-term mortality is unknown and a prospectively determined adverse events profile is lacking. Since both pancreatic resection and HIPEC may relevantly influence morbidity and mortality, this uncontrolled single-arm, open-label, phase I/II pilot trial was designed to assess the 30-day mortality rate, treatment feasibility, and adverse events connected with HIPEC after oncological pancreatic surgery.

Methods: This trial recruited patients scheduled for PDAC resection. A sample size of 16 patients receiving study interventions was estimated to establish a predefined margin of treatment-associated short-term mortality with a power of > 80%. Patients achieving complete macroscopic resection received HIPEC with gemcitabine administered at 1000 mg/m2 body surface area heated to 42 °C for 1 hour.

Results: Within 30 days after intervention, no patient died or experienced any adverse events higher than grade 3 that were related to HIPEC. Furthermore, treatment-related adverse events were prospectively documented and categorized as expected or unexpected. This trial supports that the actual mortality rate after PDAC resection and HIPEC is below 10%. HIPEC treatment proved feasible in 89% of patients allocated to intervention. Pancreatic fistulas, as key complications after pancreas surgery, occurred in 3/13 patients under risk.

Conclusion: Combined pancreas resection and gemcitabine HIPEC proved feasible and safe, with acceptable morbidity and mortality. Based on these results, further clinical evaluation can be justified.

Registration number: NCT02863471 ( http://www.clinicaltrials.gov ).

Conflict of interest statement

Markus W. Löffler and Alfred Königsrainer received a research grant from RanD S.r.l., the manufacturer of devices and consumables for HIPEC, unrelated to the present work. Can Yurttas, Philipp Horvath, Imma Fischer, Christoph Meisner, Silvio Nadalin, Ingmar Königsrainer, and Stefan Beckert declare no potential conflicts of interest.

© 2021. The Author(s).

Figures

Fig. 1.
Fig. 1.
Enrollment, allocation, follow-up, and analysis of patients during the trial (the layout was adapted from the CONSORT 2010 statement).ITT intention-to-treat group, mITT modified intention-to-treat group, PDAC pancreatic ductal adenocarcinoma
Fig. 2.
Fig. 2.
Adverse event (AE) overview in the mITT group. a Proportional distribution (%) of AEs classified according to National Cancer Institute CTCAE v.4.0, categorized as EAEs (bottom column) or UAEs (top column) [please see the Methods section (Assessment of Endpoints) for respective details]. b Proportional distribution (%) of patients experiencing (n) cumulative UAEs (left)/EAEs (right) over 30 days post-interventional follow-up. mITT modified intention-to-treat group, UAEs unexpected adverse events, EAEs expected adverse events, CTCAE Common Terminology Criteria for Adverse Events, AE adverse event

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