Frédéric Dumont1, Christophe Passot2, Jean-Luc Raoul3, Vahan Kepenekian4, Bénédicte Lelièvre5, Michelle Boisdron-Celle2, Sandrine Hiret3, Hélène Senellart3, Francois Pein6, Audrey Blanc-Lapierre7, Judith Raimbourg3, Emilie Thibaudeau8, Olivier Glehen4. 1. Department of Surgical Oncology, Institut de Cancérologie de L'Ouest, Saint Herblain, France. Electronic address: frederic.dumont@ico.unicancer.fr. 2. Oncopharmacology - Pharmacogenetics, Institut de Cancérologie de L'Ouest, Angers, France. 3. Department of Medical Oncology, Institut de Cancérologie de L'Ouest, Saint Herblain, France. 4. Department of Surgical Oncology, Centre Hospitalier Lyon Sud, Pierre Bénite, France. 5. Laboratory of Pharmacology and Toxicology, Centre Hospitalier et Universitaire, Angers, France. 6. Department of Clinical Research and Innovation, Institut de Cancérologie de L'Ouest, Saint Herblain, France. 7. Department of Biostatistics and Methodology, Institut de Cancérologie de L'Ouest, Saint Herblain, France. 8. Department of Surgical Oncology, Institut de Cancérologie de L'Ouest, Saint Herblain, France.
Abstract
OBJECTIVE: The objectives were to define the maximum tolerated dose (MTD), safety profile and pharmacokinetics (PKs) of intraperitoneal oxaliplatin delivered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in patients with advanced peritoneal carcinomatosis from gastrointestinal tract cancers. METHODS: PIPAC was applied every 4-6 weeks, for 5 cycles, in a phase I dose-escalation study using a 3 + 3 design. The first dose level was 90 mg/m2 with planned increases of 50 mg/m2 per level. Platinum concentration was measured in plasma, tissues and intraperitoneal fluid samples. The trial was registered at ClinicalTrials.gov (NCT03294252). RESULTS: Ten patients with 33 PIPAC sessions were included. No dose limiting toxicity (DLT) occurred at 90 mg/m2 and two at 140 mg/m2. The MTD was therefore set at 90 mg/m2. Overall treatment included a median number of three PIPAC sessions (range: 1-5) and secondary complete cytoreductive surgery for two patients. Overall safety showed 67 grade I-II and 11 grade III-IV toxicities, usually haematologic, digestive (nausea/vomiting, abdominal pain), and fatigue. Oxaliplatin concentrations were three- to four-fold higher in tissue in contact with aerosol than in muscle without contact. At 140 mg/m2, the plasma oxaliplatin concentration was high with Cmax and area under the curve (AUC)0-48h of 1035 μg/l and 9028 μg h/L, respectively. CONCLUSIONS: The MTD of oxaliplatin during PIPAC is 90 mg/m2. PK data demonstrate a high tumour concentration and a significant systemic absorption.
OBJECTIVE: The objectives were to define the maximum tolerated dose (MTD), safety profile and pharmacokinetics (PKs) of intraperitoneal oxaliplatin delivered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in patients with advanced peritoneal carcinomatosis from gastrointestinal tract cancers. METHODS:PIPAC was applied every 4-6 weeks, for 5 cycles, in a phase I dose-escalation study using a 3 + 3 design. The first dose level was 90 mg/m2 with planned increases of 50 mg/m2 per level. Platinum concentration was measured in plasma, tissues and intraperitoneal fluid samples. The trial was registered at ClinicalTrials.gov (NCT03294252). RESULTS: Ten patients with 33 PIPAC sessions were included. No dose limiting toxicity (DLT) occurred at 90 mg/m2 and two at 140 mg/m2. The MTD was therefore set at 90 mg/m2. Overall treatment included a median number of three PIPAC sessions (range: 1-5) and secondary complete cytoreductive surgery for two patients. Overall safety showed 67 grade I-II and 11 grade III-IV toxicities, usually haematologic, digestive (nausea/vomiting, abdominal pain), and fatigue. Oxaliplatin concentrations were three- to four-fold higher in tissue in contact with aerosol than in muscle without contact. At 140 mg/m2, the plasma oxaliplatin concentration was high with Cmax and area under the curve (AUC)0-48h of 1035 μg/l and 9028 μg h/L, respectively. CONCLUSIONS: The MTD of oxaliplatin during PIPAC is 90 mg/m2. PK data demonstrate a high tumour concentration and a significant systemic absorption.
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Authors: Robin J Lurvink; Koen P Rovers; Emma C E Wassenaar; Checca Bakkers; Jacobus W A Burger; Geert-Jan M Creemers; Maartje Los; Floortje Mols; Marinus J Wiezer; Simon W Nienhuijs; Djamila Boerma; Ignace H J T de Hingh Journal: Surg Endosc Date: 2021-11-10 Impact factor: 3.453