Short-term oxaliplatin exposure according to established hyperthermic intraperitoneal chemotherapy (HIPEC) protocols lacks effectivenessin vitroandex vivo

Abstract

Key Points: Oxaliplatin (OX)-containing solutions obtained during patient treatment with Hyperthermic intraperitoneal chemotherapy (HIPEC) unexpectedly showed low cytotoxicity in an impedance-based ex vivo cytotoxicity cell assay.  OX cytotoxicity under HIPEC conditions could be enhanced by extending drug exposure to one hour by an impedance-based ex vivo cytotoxicity cell assay.  HIPEC failed to show survival benefits in the randomized controlled PRODIGE 7 trial and was questioned in the aftermath.  Clinically relevant OX concentrations applied in conjunction with hyperthermia (42 °C) for 30 minutes, as used either at our own medical center or according to the PRODIGE 7 trial, proved predominantly ineffective, when used according to HIPEC routines in an impedance-based in vitro cytotoxicity cell assay.  Respective findings were corroborated in two different cell lines and by two established end-point assays, showing that 50 % cell death could not be reached by the same HIPEC treatment with OX, in contrast to continuous drug exposure.  As potentially relevant factor, the thickness of the exposed cell layer was identified, requiring at least ~100 µm penetration depth for our model to indicate effectiveness.  Additionally, we show relevant cell shrinkage by two drug diluents used either at our own medical center or according to the PRODIGE 7 trial, potentially associated with fluid shifts out of the cell and impaired drug effects.  Our own as well as recent findings by Ubink et al. (Br J Surg. 2019. doi: 10.1002/bjs.11206) support the notion that lacking effectiveness of OX HIPEC may explain the negative PRODIGE 7 trial results.

Preclinical In Vivo-Models to Investigate HIPEC; Current Methodologies and Challenges

“…For example, Kirstein et al showed that the combination of heat (42 °C) and oxaliplatin was significantly more effective at a treatment duration of 2 h compared to 30 min [ 11 ]. This was underlined by the study performed by Löffler et al, concluding that 30-min exposure to clinical oxaliplatin concentrations frequently fails to induce 50% cell death and that oxaliplatin should be applied longer for generating an adequate amount of cell death [ 107 ]. In a different study by Murata et al three different gastric cancer cell lines were treated with either 5-FU, mitomycin C or cisplatin for a duration of 30 or 60 min.…”

Cytoreductive surgery and HIPEC in colorectal cancer—did we get hold of the wrong end of the stick?

“…As convincing preclinical evidence to inform clinical practice remains the exception such research frequently post-dates the clinical use of drugs for HIPEC (cf. studies with oxaliplatin [12,13] or mitomycin C (MMC) [14]).…”

“…Aiming to compile evidence to understand the underlying mechanisms for failure of certain HIPEC protocols, our group has recently gathered preliminary evidence (available as a preprint) suggesting that during short-term HIPEC, oxaliplatin is unable to penetrate deep enough into cell layers (~100 µm) to cause relevant cell death even in micrometastases [12]. Likewise, Ubink et al have evaluated clinically used HIPEC protocols in an in vitro CRC organoid model [13], where both MMC and oxaliplatin were shown ineffective to induce robust cell death at commonly attained drug dosages reached during HIPEC in vivo, suggesting there may be more generic issues.…”