• Ruben A G van Eerden, Nadine L de Boer, Job P van Kooten, Checca Bakkers, Michelle V Dietz, CreemersGeert-Jan MGMDepartment of Medical Oncology, Catharina Cancer Institute, Eindhoven, the Netherlands., Sanne M Buijs, Ramon Bax, Femke M de Man, Robin J Lurvink, Marjolein Diepeveen, Alexandra R M Brandt-Kerkhof, Esther van Meerten, Stijn L W Koolen, de HinghIgnace H J TIHJTDepartment of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands., Cornelis Verhoef, MathijssenRon H JRHJDepartment of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., and BurgerJacobus W AJWADepartment of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands..
• Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
• Br J Surg. 2023 Oct 10; 110 (11): 150215101502-1510.

BackgroundPatients with colorectal peritoneal metastases who are not eligible for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) owing to extensive peritoneal disease have a poor prognosis. It was hypothesized that these patients may benefit from the addition of intraperitoneal irinotecan to standard palliative systemic chemotherapy.MethodsThis was a classical 3 + 3 phase I dose-escalation trial in patients with colorectal peritoneal metastases who were not eligible for CRS-HIPEC. Intraperitoneal irinotecan was administered every 2 weeks, concomitantly with systemic FOLFOX (5-fluorouracil, folinic acid, oxaliplatin)-bevacizumab. The primary objective was to determine the maximum tolerated dose and dose-limiting toxicities. Secondary objectives were to elucidate the systemic and intraperitoneal pharmacokinetics, safety profile, and efficacy.ResultsEighteen patients were treated. No dose-limiting toxicities were observed with 50 mg (4 patients) and 75 mg (9 patients) intraperitoneal irinotecan. Two dose-limiting toxicities occurred with 100 mg irinotecan among five patients. The maximum tolerated dose of intraperitoneal irinotecan was established to be 75 mg, and it was well tolerated. Intraperitoneal exposure to SN-38 (active metabolite of irinotecan) was high compared with systemic exposure (median intraperitoneal area under the curve (AUC) to systemic AUC ratio 4.6). Thirteen patients had a partial radiological response and five had stable disease. Four patients showed a complete response during post-treatment diagnostic laparoscopy. Five patients underwent salvage resection or CRS-HIPEC. Median overall survival was 23.9 months.ConclusionAdministration of 75 mg intraperitoneal irinotecan concomitantly with systemic FOLFOX-bevacizumab was safe and well tolerated. Intraperitoneal SN-38 exposure was high and prolonged. As oncological outcomes were promising, intraperitoneal administration of irinotecan may be a good alternative to other, more invasive and costly treatment options. A phase II study is currently accruing.© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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