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

Background: The success of cisplatin- based ( Platinol, Bristol- Myers Squibb Company, New York, NY, USA) chemotherapy for testicular cancer comes at the price of long- term and late effects related to healthy tissue damage. We assessed and modelled serum platinum ( Pt) decay after chemotherapy and determined relationships between long- term circulating Pt levels and known late effects. Patients and methods: In 99 testicular cancer survivors, treated with cisplatin- based chemotherapy, serum and 24- h urine samples were collected during follow- up ( 1- 13 years after treatment). To build a population pharmacokinetic model, measured Pt data were simultaneously analysed, together with cisplatin dose, age, weight and height using the NONMEM software. Based on this model, area under the curve between 1 and 3 years after treatment ( Pt AUC1- 3 years) was calculated for each patient. Predicted long- term Pt exposure was related to renal function and to late effects of treatment assessed median 9 ( 3- 15) years after chemotherapy. Results: Decay of Pt was best described by a two- compartment model. Mean terminal T1/ 2 was 3.7 ( range 2.5- 5.2) years. Pt AUC1- 3 years correlated with cumulative cisplatin dose, and creatinine clearance before and 1 year after treatment. Patients with paraesthesia had higher Pt AUC1- 3 years ( 30.9 versus 27.0 mu g/ l month) compared with those without paraesthesia ( P = 0.021). Patients with hypogonadism, elevated LDL- cholesterol levels or hypertension also had higher Pt AUC1- 3 years. Conclusions: Renal function before and after cisplatin treatment is an important determinant of long- term Pt exposure. Known long- term effects of testicular cancer treatment, such as paraesthesia, hypogonadism, hypercholesterolaemia and hypertension, are associated with long- term circulating Pt exposure.