title: Cardiovascular disease after treatment for Hodgkin's lymphoma: an analysis of nine collaborative EORTC-LYSA trials.
abstract: BACKGROUND
  Cardiovascular disease after treatment is an important concern in cancer survivors. However, knowledge of cardiotoxicity is limited by the retrospective nature of data, which often does not contain details of treatment exposure. To facilitate individual risk counselling of patients, we aimed to quantify the effect of anthracyclines, vinca-alkaloids, and radiotherapy on the risk of cardiovascular disease in patients treated for Hodgkin's lymphoma.
  
  
  METHODS
  In 2009-10, a Life Situation Questionnaire (LSQ) was distributed to patients by mail to assess late-onset effects of Hodgkin's lymphoma treatment in patients who were included in nine successive European Organisation for Research and Treatment of Cancer (EORTC) and the Groupe d'Etude des Lymphomes de l'Adulte (GELA, now renamed LYSA) randomised trials between 1964 and 2004. We reconstructed the mean radiation doses to the heart and carotid arteries and the cumulative doses of anthracyclines and vinca-alkaloids for all patients. Incidence of cardiovascular disease was reported during follow-up and updated through the LSQ. We applied Cox proportional hazards regression analyses to quantify the effect of chemotherapy and radiation on the risk of a first cardiovascular disease event.
  
  
  RESULTS
  Information of primary treatment was complete for 6039 patients (median age at diagnosis 30 years [IQR 23-40]; median length of follow-up 9 years [6-14]). 1919 patients responded to the LSQ. 1238 first cardiovascular events were recorded in 703 patients, most were ischaemic heart disease (132 [19%]), congestive heart failure (85 [12%]), arrhythmia (110 [16%]), and valvular disease (77 [11%]). The mean heart radiation dose per 1 Gy increase (HR 1·015 [95% CI 1·006-1·024], p=0·0014) and the dose of anthracyclines per 50 mg/m(2) increase in cumulative dose (1·077 [1·021-1·137], p=0·0064) were significant predictors of cardiovascular disease. Cumulative dose of vinblastine (unadjusted model p=0·77), vincristine (p=0·36), and mean radiation dose to the left (p=0·41) or right (p=0·70) internal carotid artery did not predict for cardiovascular events.
  
  
  CONCLUSIONS
  Quantification of the increased cardiovascular risk with specific doses of radiation and anthracycline exposure will enable a quantitative assessment of the optimum combination of systemic therapy and radiation, which will help clinicians to balance the risks and benefits of different regimens for individual patients.
  
  
  BACKGROUND
  Rigshospitalet Research Committee, the EORTC Cancer Research Fund, and the Sally Snowman Survivorship Fellowship.
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark. Electronic address: dra.maraldo@gmail.com.
authors.forename: Maja V
authors.initials: MV
authors.lastname: Maraldo
authors.affiliation: European Organisation of Research and Treatment of Cancer, Brussels, Belgium.
authors.forename: Francesco
authors.initials: F
authors.lastname: Giusti
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Ivan R
authors.initials: IR
authors.lastname: Vogelius
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark; Niels Bohr Institute, Department of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Lundemann
authors.affiliation: Department of Internal Medicine, VU University Medical Centre, Amsterdam, Netherlands.
authors.forename: Marleen A E
authors.initials: MA
authors.lastname: van der Kaaij
authors.affiliation: National Cancer Institute, Cairo University, Cairo, Egypt.
authors.forename: Safaa
authors.initials: S
authors.lastname: Ramadan
authors.affiliation: European Organisation of Research and Treatment of Cancer, Brussels, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Meulemans
authors.affiliation: Centre de Traitement des Données du Cancéropôle Nord-Ouest, Centre François Baclesse, Caen, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Henry-Amar
authors.affiliation: Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Berthe M P
authors.initials: BM
authors.lastname: Aleman
authors.affiliation: Department of Hematology, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Raemaekers
authors.affiliation: Department of Radiation Oncology, ZNA Middelheim and University of Antwerp, Antwerp, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Meijnders
authors.affiliation: Department of Radiation Oncology, Champalimaud Cancer Centre, Lisbon, Portugal.
authors.forename: Elisabeth C
authors.initials: EC
authors.lastname: Moser
authors.affiliation: Department of Hematology, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Hanneke C
authors.initials: HC
authors.lastname: Kluin-Nelemans
authors.affiliation: Department of Hematology, CHU de Nancy Hôpital de Brabois, Nancy, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Feugier
authors.affiliation: Department of Hematology, CHU de Dijon Complexe du Bocage, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Casasnovas
authors.affiliation: European Organisation of Research and Treatment of Cancer, Brussels, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fortpied
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark; Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Lena
authors.initials: L
authors.lastname: Specht
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D005260:Female; D006689:Hodgkin Disease / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D011829:Radiation Dosage; D011878:Radiotherapy / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D012307:Risk Factors; D017741:Survivors; D014748:Vinca Alkaloids / Q000009:adverse effects; D055815:Young Adult
chemical_list: D018943:Anthracyclines; D014748:Vinca Alkaloids