Relationship between persistent neurotoxicity and long-term platinum exposure after treatment with cisplatin

Abstract

2546 Background: We aimed to assess relationships between the severity of persistent neuropathy and long-term platinum exposure in patients previously treated with cisplatin. Methods: Twenty patients, treated with a cisplatin containing regimen 18 to 75 months before participating in this study, were included. Sensory nerve function in hands and feet was evaluated using vibration threshold (VT) determination. Platinum levels in plasma and plasma ultrafiltrate were assessed using inductively coupled plasma mass spectrometry (ICP- MS). Possible factors affecting sensory nerve function or platinum retention were collected, including cumulative dose, follow-up time, route of administration, renal function, glutathione S-transferase (GST) genotypes, co-administration of sodium thiosulfate (STS with intra-arterial (i.a.) cisplatin), and co-morbidity (alcoholism and diabetes). Results were evaluated using non linear mixed effects modelling. Results: Patients (9 testis, 8 head-neck, 1 NSCLC, 1 SCLC, and 1 yolk sac) were treated with a cumulative dose of 300–600 mg·m-2. Five patients received STS. Platinum plasma concentrations ranged between 142.4–1154 ng·L-1of which on average14.8% was recovered in ultrafiltrate. Platinum levels decreased with a half-life of 21.7 months and were related to the cumulative dose. Platinum levels were reduced by 60% with i.a. cisplatin and co-administration of STS (p=0.002). The hand-VT decreased with time (t1/2=19.9 months) and was related to cumulative dose and to alcohol use (p=0.06). Moreover, the half-life of recovery of the hand-VT was related to the elimination half-life of platinum, albeit non-significant. In contrast, the feet-VT did not improve over time and did not show an association with cumulative dose or any of the other factors. GST genotypes and renal function were not related to VT and platinum levels. Conclusions: Our data suggest that plasma platinum levels are related to follow-up time, cumulative dose, and STS use. The data show that neuropathy in the feet might be irreversible in contrast to the hand-VT, which was also related to cumulative dose and alcohol use. Whether recovery of neuropathy was related to platinum elimination remains to be established. No significant financial relationships to disclose.