Cisplatin-induced nephrotoxicity in hyperthermic intraperitoneal chemotherapy (HIPEC) is mitigated by sodium thiosulfate: Clinical and toxicotranscriptomic results of a prospective trial.

Abstract

5570 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC). Unfortunately, cisplatin is associated with significant renal toxicities. Sodium thiosulfate (ST) has been suggested as a nephroprotectant for patients undergoing HIPEC with cisplatin. Methods: A feasibility trial ( ClinicalTrials.gov: NCT01970722) evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during optimal cytoreductive surgery (CRS) in patients with EOC and endometrial cancer (n = 40), with or without ST. Twenty-one patients received no sodium-thiosulfate (nST group), and nineteen patients received sodium thiosulfate (ST group). Toxicities were reported according to CTCAE v. 5. Progression-free survival was followed. Normal tissue biopsies were collected intra-operatively immediately following HIPEC and cisplatin exposure in a subset of patients (n = 21), and profiled with transcriptomic sequencing to identify RNAseq signatures correlating with toxicities. Hierarchical cluster analyses identified distinct transcriptomic signatures in post-HIPEC normal samples of patients with renal AEs (rAEs) compared to no renal AEs (nrAEs). KEGG pathway analysis identified up- or downregulated gene sets using GSEA. Results: Forty patients had HIPEC at time of optimal CRS. Renal toxicities were higher in the nST group (no sodium thiosulfate) compared to the ST group. nST patients had 17% any grade, and 9% Grade 3 AEs for acute and chronic kidney injuries. In contrast, ST patients suffered 0% renal AEs. rAE patients demonstrated upregulation of immune signaling pathways (Toll-like receptor, Natural killer cell, Nod-like receptor); and downregulation of metabolic pathways. Top upregulated genes in rAE patients included immune (e.g. neutrophil) related genes, while downregulated genes included metabolism genes. Kaplan-Meier curves demonstrated improved PFS in primary ovarian cancer patients undergoing HIPEC who were treated with ST vs no ST (p = 0.04, NR vs 13.4 mo). Conclusions: HIPEC with cisplatin results in significant renal toxicities. The mechanisms of cisplatin-induced nephrotoxicity in HIPEC are immune-related and reflect reduced metabolism. Sodium thiosulfate abrogated renal toxicities and did not decrease PFS. Clinical trial information: NCT01970722.