Long-term exposure to circulating platinum is associated with late effects of treatment in testicular cancer survivors

Abstract

Cisplatin is an essential part of testicular cancer treatment. We investigated whether long-term exposure to circulating platinum (Pt) plays a role in the development of late effects in survivors. We assessed Pt decay in samples collected 1–13 years after chemotherapy. Renal function is a strong determinant of exposure to Pt. Higher exposure to Pt is associated with an increased prevalence of adverse effects hypogonadism and hypertension.

Residual Platinum Concentrations in Post-Cancer Chemotherapy and Healthy Control Populations Using an Automated, 96-Well Plate Method and Inductively Coupled Plasma Mass Spectrometry

“…Previously published methods for quantifying low Pt concentrations in serum represented high-quality research assays but were difficult to implement for routine use in the clinical laboratory (4)(5)(6)14). Original methods were based on the measurement of Pt in plasma ultrafiltrates and used lengthy integration times to achieve the needed sensitivity (6).…”

“…Although it is well established that a cumulative dose of platinum administered intravenously is associated with a number of these adverse effects, it is also recognized that in European populations, platinum concentrations remain significantly increased in serum years after chemotherapy completion (2)(3)(4). Moreover, Brouwers et al (5) showed that these circulating platinating agents remain partly reactive.…”

“…Sprauten et al (3) recently documented a significant relationship between increasing concentration of residual serum platinum and the severity of neurotoxicity after adjusting for cumulative dose. Thus, it becomes increasingly apparent that quantification of long-term serum platinum concentrations in patients treated with platinumbased chemotherapy may help identify individuals at highest risk of late effects as well as elucidate possible mechanisms (4). Additionally, the extent to which persistent serum platinum concentrations might affect the actions of essential trace elements (e.g., calcium, magnesium) or result in chronic endothelial activation and vascular damage has also not been systematically or comprehensively addressed (1).…”

“…The MVX-7100 low-volume autosampler was used for sample introduction into the ICPMS equipped with a 1.5-mL sample syringe and 2.0-mL injection syringe. Before each batch, the sample loop and injection loop were rinsed using a sequence of 1.25 mL isopropyl alcohol, 1.25 mL 1% NH 4 OH, and 1.25 mL 1% HNO 3 before 3 full syringe primes of a makeup fluid containing 0.5% HNO 3 with 0.05% Triton X-100. A 500-μL sample loop was used to inject 450 μL of sample with airgaps at the front and the back to isolate the sample from the makeup solution and prevent mixing.…”

The Sound of Silence: A Proxy for Platinum Toxicity

“…Hypothesized ongoing damage of nerve fibers and/or blood vessels was supported by a comprehensive Dutch study on residual platinum, applied cumulative dose, and renal function combined with careful phenotyping of long-term outcomes like paresthesia, hypogonadism, high LDL cholesterol, and hypertension. 16 Hypertension was, among several other toxicities, significantly associated with higher exposure to residual platinum levels. We thereby assume the described association between hearing impairment and hypertension reflects two separate outcomes of the initial treatment, with hearing impairment being more stable after the initial damage caused by the peak cisplatin concentration, whereas hypertension probably was aggravated by ongoing endothelial damage by long-term circulating residual platinum.…”