Abstract 3194: Cisplatin-DNA adduct formation in patients receiving cisplatin +/- sodium thiosulphate (STS) in the SIOPEL 6 randomized phase III trial
Authors: Veal Gareth J. , Ronghe Milind , Morland Bruce , Neuwelt Edward , Maibach Rudolf , Brock Penelope 
Published: July 2016

Background: The SIOPEL 6 randomised phase III trial was designed to investigate the efficacy of sodium thiosulphate (STS) in reducing ototoxicity in patients receiving cisplatin monotherapy for standard-risk hepatoblastoma. Preliminary results from the trial recently presented at ASCO indicated comparable response rates between the two study arms. The trial has now completed patient recruitment, with final evaluation of hearing loss at ≥3.5 years of age awaited as the primary endpoint of the trial. As part of the clinical study, blood samples were collected pre-treatment and 24 hours following cisplatin administration, to investigate the potential impact of STS on the formation of platinum-DNA adduct levels in leucocytes.

Patients and methods: Whole blood samples (5-10ml) were taken prior to cisplatin treatment and 24 hours following the start of a 6 hour cisplatin infusion, with STS administered 6 hours after the end of cisplatin administration in patients randomised to receive STS. Samples were collected in EDTA blood tubes and frozen at -20°C or -80°C prior to transport to Newcastle for analysis. DNA was isolated from whole blood using Qiagen DNA blood Maxi kits and the concentration of DNA in each sample quantified by UV absorption. DNA samples were diluted in 3.5% nitric acid and hydrolyzed overnight at 70°C. Platinum-DNA adduct levels were determined by ICP-MS analysis, with results expressed in units of nmoles platinum/g DNA.

Results: Blood samples were collected from a total of 37 patients, with 22/37 (59%) patients having received cisplatin followed by STS and 15/37 (41%) patients cisplatin alone. A significant difference in median platinum-DNA adduct levels was observed in patients receiving cisplatin followed by STS (median: 6.7 nmol/g DNA; range: 4.2 - 14.0), as compared to patients receiving cisplatin alone (median: 13.5 nmol/g DNA; range: 4.3 - 165.7) (P = 0.0011).

Conclusion: Results indicate that the formation and/or longevity of platinum-DNA adducts determined in whole blood samples collected 24 hours following cisplatin administration are influenced by the co-administration of STS, with significantly higher levels observed in patients receiving cisplatin alone. Bearing in mind the comparable response data reported between the two randomisation study arms, these data would indicate that platinum-DNA adduct formation in leucocytes may act as a surrogate marker, providing novel insights into the mechanism of the otoprotective effects of STS when used in combination with cisplatin.

Acknowledgements: Work supported by Cancer Research UK, the North of England Children's Cancer Research Fund and the Experimental Cancer Medicine Centre Network.

Citation Format: Gareth J. Veal, Milind Ronghe, Bruce Morland, Edward Neuwelt, Rudolf Maibach, Penelope Brock. Cisplatin-DNA adduct formation in patients receiving cisplatin +/- sodium thiosulphate (STS) in the SIOPEL 6 randomized phase III trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3194.