To the best of our knowledge, this is the first study demonstrating that long-term serum platinum levels are significantly associated with the severity of neurotoxicity 5 to 20 years after cisplatin-based chemotherapy. Importantly, the relationship remained significant after adjustment for initial cisplatin dose. Serum platinum quartiles were positively associated with overall neurotoxicity and ototoxicity as assessed by total SCIN scores at Surveys I and II (P trend = .002 and .032, respectively), as were most individual symptoms.
Strengths of our study include a large well-characterized cohort of TCSs with long-term follow-up and detailed information regarding cancer therapy. All men were treated at the same hospital and underwent standardized examinations at Surveys I and II. The high participation rate ensures validity of our findings.
Although our study is derived from the largest cohort of TCSs to date,5,10,15,22,27
numbers of patients available in various subgroup analyses remain small, limiting statistical power. Serum platinum levels were available for Survey I only, precluding calculation of platinum elimination rates. The questionnaires, however, were collected at both Survey I and Survey II. Interpretation of our findings would have been stronger if the symptom measurements and serum platinum levels had been measured in a longitudinal fashion at both surveys, also including objective measurements.
Reliance on self-reported symptoms without objective measurements is a limitation of this study. Ototoxicity as recorded on the SCIN was previously validated among these patients through objective measurements.39
Neurologic tests, however, were not performed in our study. Other studies observed that, compared with self-report, prevalence of adverse effects may be higher when measured objectively.39,46
Most patients received cisplatin in combination with bleomycin, usually regarded as the principal cause of Raynaud's phenomenon. However, cisplatin might also contribute to cold-induced vasospasms. Vogelzang et al47
reported the incidence of Raynaud's phenomenon to be 21% after vinblastine and bleomycin compared with 41% after therapy with CVB. In the comprehensive report by Brydoy et al,15
Raynaud's phenomenon was not associated with bleomycin in contrast to a dose-dependent effect observed for cisplatin and dose-intensive cisplatin-based chemotherapy.
Studies performed within 15 months after cisplatin administration,48–51
show increased platinum levels in most organs. In human autopsies conducted 4 to 867 days after the last cisplatin dose, platinum concentrations were highest in dorsal root ganglia and lowest in tissues protected by the blood-brain barrier, in line with observations of sensory neuropathies and histopathologically documented peripheral nerve damage.48
Subsequent rates of decline in tissue platinum are lowest in sensory ganglia, sural nerves, and liver.48
Previous data have suggested that both the incidence and severity of neurotoxicity are mainly determined by the cumulative cisplatin dose, and are determined for ototoxicity also by the dose-intensive regimen.15,52,53
However, in our study, the highest long-term serum platinum levels were most strongly correlated with the severity of SCIN, even when adjusted for initial cisplatin dose. A possible explanation for this finding is that ongoing exposure to low-level platinum in neural tissue, as well as any residual systemic effects, may limit resolution of the acute and dose-dependent sensory neuropathy, hypothetically also contributing to ongoing damage.54
The biokinetic behavior of platinum closely resembles that of other toxic metals (eg, mercury and chromium55,56
) in which serum and urine concentrations also correlate with toxic outcomes.55,57
Importantly, Brouwers et al23
showed that approximately 10% of platinum remains reactive over the long term.
Similar to prior studies,23,24,26
we found a significant relationship between initial dose and platinum levels and an inverse relationship between time since administration and platinum levels. Future efforts evaluating the potential toxic impact of circulating serum platinum would benefit from the prospective collection of larger sample volumes, because available amounts did not permit determination of reactive platinum hypothesized by some to be the pharmacologically and toxicologically active species.23
Several studies of TCSs have demonstrated ongoing endothelial changes for more than 10 years after cisplatin administration, indicating a possible prolonged effect of residual platinum.6,54,58
In particular, Vaughn et al,54
showed endothelial damage in TCSs at a median of 5.1 years after cisplatin-based treatment. These investigators postulated that the increased risk of CVD in TCSs could be due partly to persistent exposure of endothelial cells to circulating platinum. Other studies have shown an increased risk for late CVD in TCSs given cisplatin-based chemotherapy.6,10,12,59
It may also contribute to increased risk of metabolic syndrome in TCSs;5,6
however, results are inconclusive.10
have shown significantly increased risks of solid tumors and leukemia9
among cisplatin-treated TCSs. Whether cisplatin in tissue deposits or in circulating form, alone or with other agents, may serve an initiating or promoting carcinogenic role is not known.
Our results suggest that interventional strategies reducing long-term platinum levels may show promise for lessening long-term neurotoxicity, with the importance of further studies in this area recently underscored by a National Cancer Institute panel.61
Currently, to the best of our knowledge, there are no agents that ameliorate the clinical neurotoxicity of platinating agents. According to a recent Cochrane Database review,62
information on possible neuroprotective agents, such as acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxycarbazepine, or vitamin E are insufficient to conclude that they “prevented or limited neurotoxicity of platinum drugs among human patients.”
Importantly, we do not question the use of cisplatin in the treatment of metastatic TC, because this drug is still the cornerstone of the chemotherapy that rendered this cancer a model for a curable neoplasm.3,4
Whether carboplatin would have less long-term toxicity is unknown; however, carboplatin would decrease the cure rate.63
Nonetheless, we demonstrate that long-term serum levels of platinum correlate with the severity of neurotoxicity 5 to 20 years after chemotherapy in TCSs. Although chemotherapy-induced neuropathies are not life threatening, symptoms can have a debilitating effect on patients' quality of life and functioning. Increasing knowledge about the long-term effects of circulating platinum underscores the importance of interventional strategies to minimize platinum-related neurotoxicity and ototoxicity and potentially fatal events such as myocardial infarction and secondary malignancies. To validate our findings and to elucidate the underlying mechanisms of toxicities related to the effect of reactive platinum, we emphasize the importance of further studies on the impact of residual platinum in an independent large cohort of platinum-treated survivors of cancer.