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.


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 µg/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.
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
H
H
Boer
Department of Hospital Pharmacy, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
J H
JH
Proost
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
J
J
Nuver
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
S
S
Bunskoek
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
J Q
JQ
Gietema
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
B M
BM
Geubels
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
R
R
Altena
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
N
N
Zwart
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
S F
SF
Oosting
Department of Epidemiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
J M
JM
Vonk
Department of Vascular Medicine, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
J D
JD
Lefrandt
Department of Hospital Pharmacy, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
D R A
DR
Uges
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
C
C
Meijer
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
E G E
EG
de Vries
Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands j.a.gietema@umcg.nl.
J A
JA
Gietema
D000328:Adult; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000151:congenital / Q000175:diagnosis; D006973:Hypertension / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D010984:Platinum / Q000097:blood*; D013736:Testicular Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
D010984:Platinum; D002945:Cisplatin
BEP; germ cell cancer; long-term toxicity; nephrotoxicity; platinum