title: Renal impairment and late toxicity in germ-cell cancer survivors.
abstract: BACKGROUND
  Treatment with bleomycin-etoposide-cisplatin (BEP) impairs renal function and increases the risk of late cardiovascular disease (CVD) and death. We investigated the influence of BEP on glomerular filtration rate (GFR) and assessed the importance of GFR changes on CVD and death in a large cohort of germ-cell cancer survivors.
  
  
  METHODS
  BEP-treated patients (N = 1206) were identified in the Danish DaTeCa database, and merged with national registers to identify late toxicity. GFR were measured (51Cr-EDTA clearance) before and after treatment and at 1, 3 and 5-year follow-up. The influence of BEP on GFR was evaluated with a linear mixed model. Risk factors for late toxicity were identified by a landmark analysis adjusting for covariates. The cohort was compared with the background population with standardized hospitalization/mortality rates.
  
  
  RESULTS
  GFR changed (ΔGFR) -11.3%, -15.4% and -25.9% after three, four and five+ cycles of BEP. For patients with impaired renal function before treatment the changes were 4.3%, 0.0% and -12.8%, respectively. During follow-up a significant rebound of GFR was documented. Compared with the background population, all patients, irrespective of renal function, had an increased risk of CVD and death. This risk depended on chronic kidney disease stage before treatment but not after treatment. ΔGFR had no influence on risk of late toxicity [death: hazard ratio (HR) 1.06, P = 0.50; CVD: HR 0.97, P = 0.61].
  
  
  CONCLUSIONS
  Renal function after BEP is closely related to number of cycles, but the changes in GFR are partly reversible and have no impact on risk of CVD or death.
authors.affiliation: Department of Oncology 5073, Copenhagen University Hospital, Rigshospitalet, Copenhagen. Electronic address: jakob.lauritsen@regionh.dk.
authors.forename: J
authors.initials: J
authors.lastname: Lauritsen
authors.affiliation: Department of Oncology 5073, Copenhagen University Hospital, Rigshospitalet, Copenhagen.
authors.forename: M S
authors.initials: MS
authors.lastname: Mortensen
authors.affiliation: Department of Oncology 5073, Copenhagen University Hospital, Rigshospitalet, Copenhagen.
authors.forename: M G G
authors.initials: MGG
authors.lastname: Kier
authors.affiliation: Finsen Laboratory, Rigshospitalet and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen Biocenter, Copenhagen.
authors.forename: I J
authors.initials: IJ
authors.lastname: Christensen
authors.affiliation: Department of Oncology, Aarhus University Hospital, Aarhus.
authors.forename: M
authors.initials: M
authors.lastname: Agerbaek
authors.affiliation: Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Kongens Lyngby, Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Department of Oncology 5073, Copenhagen University Hospital, Rigshospitalet, Copenhagen.
authors.forename: G
authors.initials: G
authors.lastname: Daugaard
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D001761:Bleomycin / Q000009:adverse effects / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use; D005047:Etoposide / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy*; D051437:Renal Insufficiency / Q000139:chemically induced*; D055815:Young Adult
chemical_list: D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin
keywords: BEP; CVD; germ-cell cancer; late effects; nephrotoxicity