Body surface area-based versus concentration-based intraperitoneal perioperative chemotherapy in a rat model of colorectal peritoneal surface malignancy: pharmacologic guidance towards standardization.

Jirka Cops,Robert Carleer,Paul Sugarbaker,Kurt Van der Speeten,Lieselotte Lemoine,Elsy Thijssen,Peter Van Eyken,Veerle Lemmens

doi:10.18632/oncotarget.26667

Jirka Cops, Robert Carleer + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.26667

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Abstract

Worldwide, cytoreductive surgery (CRS) and hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) are used in current clinical practice for colorectal peritoneal surface malignancy (PSM) treatment. Although, there is an acknowledged standardization regarding the CRS, we are still lacking a much-needed standardization amongst the various intraperitoneal (IP) chemotherapy protocols, including the HIPEC dosing regimen. We should rely on pharmacologic evidence building towards such a standardization. The current IP chemotherapy dosing regimens can be divided into body surface area (BSA)-based and concentration-based protocols. A preclinical animal study was designed to evaluate pharmacologic advantage (PA), efficacy and survival. WAG/Rij rats were IP injected with the rat colonic carcinoma cell line CC-531. Animals were randomized into three groups: CRS alone or CRS combined with oxaliplatin-based HIPEC (either BSA- or concentration-based). There was no difference in PA between the two groups (p=0.283). Platinum concentration in the tumor nodule was significantly higher in the concentration-based group (p<0.001). Median survival did not differ between the treatment groups (p<0.250). This preclinical study, in contrast to previous thinking, clearly demonstrates that the PA does not provide any information about the true efficacy of the drug and emphasizes the importance of the tumor nodule as pharmacologic endpoint.

Highlights

Worldwide, cytoreductive surgery (CRS) and hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) are used in current clinical practice for selected patients diagnosed with peritoneal surface malignancy (PSM) of colorectal origin [1, 2]
To determine in vivo toxicity of the CC-531 cell line, rats were treated with CRS and HIPEC with increasing doses of oxaliplatin (40 – 150 mg/m2 in 2 L/ m2)
We report that there is no difference in pharmacologic advantage (PA), defined as the ratio of Area-under-the curve (AUC) peritoneal fluid over AUC plasma, between BSAbased and concentration-based HIPEC

Summary

Introduction

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) are used in current clinical practice for selected patients diagnosed with peritoneal surface malignancy (PSM) of colorectal origin [1, 2]. This combined treatment modality has resulted in significant survival benefit, with a median overall survival of 41.7 months (results presented at the ASCO annual meeting in Chicago) [3]. We should rely on validated analytical assays and well-designed preclinical studies to build pharmacologic data towards improved and standardized HIPEC regimens. An experimental study was performed to pharmacologically evaluate toxicity, efficacy and survival of body surface area (BSA)-based and concentration-based intraperitoneal (IP) chemotherapy in a rat model of colorectal PSM

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