title: Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma: an analysis from the St Jude Lifetime Cohort Study.
abstract: BACKGROUND
  The magnitude of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma is not known. Using medically ascertained data, we applied the cumulative burden metric to compare chronic cardiovascular health conditions in survivors of Hodgkin's lymphoma and general population controls.
  
  
  METHODS
  For this study, participant data were obtained from two ongoing cohort studies at St Jude Children's Research Hospital: the St Jude Lifetime Cohort Study (SJLIFE) and the St Jude Long-term Follow-up Study (SJLTFU). SJLIFE is a cohort study initiated on April 27, 2007, to enable longitudinal clinical evaluation of health outcomes of survivors of childhood cancer treated or followed at St Jude Children's Research Hospital, and SJLTFU is an administrative system-based study initiated in 2000 to collect outcome and late toxicity data for all patients treated at the hospital for childhood cancer. The patient cohort for our study was defined as patients treated at St Jude Children's Research Hospital who reached 18 years of age and were at least 10 years post-diagnosis of pathologically confirmed primary Hodgkin's lymphoma. Outcomes in the Hodgkin's lymphoma survivors were compared with a sample of SJLIFE community control participants, aged 18 years or older at the time of assessment, frequency-matched based on strata defined by 5-year age blocks within each sex, who were selected irrespective of previous medical history. All SJLIFE participants underwent assessment for 22 chronic cardiovascular health conditions. Direct assessments, combined with retrospective clinical reviews, were used to assign severity to conditions using a modified Common Terminology Criteria of Adverse Events (CTCAE) version 4.03 grading schema. Occurrences and CTCAE grades of the conditions for eligible non-SJLIFE participants were accounted for by multiple imputation. The mean cumulative count (treating death as a competing risk) was used to estimate cumulative burden.
  
  
  RESULTS
  Of 670 survivors treated at St Jude Children's Research Hospital, who survived 10 years or longer and reached age 18 years, 348 were clinically assessed in the St Jude Lifetime Cohort Study (SJLIFE); 322 eligible participants did not participate in SJLIFE. Age and sex frequency-matched SJLIFE community controls (n=272) were used for comparison. At age 50 years, the cumulative incidence of survivors experiencing at least one grade 3-5 cardiovascular condition was 45·5% (95% CI 36·6-54·3), compared with 15·7% (7·0-24·4) in community controls. The survivor cohort at age 50 experienced a cumulative burden of 430·6 (95% CI 380·7-480·6) grade 1-5 and 100·8 (77·3-124·3) grade 3-5 cardiovascular conditions per 100 survivors; these numbers were appreciably higher than those in the control cohort (227·4 [192·7-267·5] grade 1-5 conditions and 17·0 [8·4-27·5] grade 3-5 conditions per 100 individuals). Myocardial infarction and structural heart defects were the major contributors to the excess grade 3-5 cumulative burden in survivors. High cardiac radiation dose (≥35 Gy) was associated with an increased proportion of grade 3-5 cardiovascular burden, whereas increased anthracyline dose was not.
  
  
  CONCLUSIONS
  The true effect of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma is reflected in the cumulative burden. Survivors aged 50 years will experience more than two times the number of chronic cardiovascular health conditions and nearly five times the number of more severe (grade 3-5) cardiovascular conditions compared with community controls and, on average, have one severe, life-threatening, or fatal cardiovascular condition. The cumulative burden metric provides a more comprehensive approach for assessing overall morbidity compared with currently used cumulative incidence based analytic methodologies, and will assist clinical researchers when designing future trials and refining general practice screening guidelines.
  
  
  BACKGROUND
  US National Cancer Institute, St Baldrick's Foundation, and American Lebanese Syrian Associated Charities.
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA. Electronic address: nickhill.bhakta@stjude.org.
authors.forename: Nickhill
authors.initials: N
authors.lastname: Bhakta
authors.affiliation: School of Public Health, University of Alberta, Edmonton, AB, Canada.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Yeo
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Malek
authors.initials: M
authors.lastname: Baassiri
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ehrhardt
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Deo K
authors.initials: DK
authors.lastname: Srivastava
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Monika L
authors.initials: ML
authors.lastname: Metzger
authors.affiliation: Department of Radiation Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Krasin
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Kirsten K
authors.initials: KK
authors.lastname: Ness
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Hudson
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA; School of Public Health, University of Alberta, Edmonton, AB, Canada.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yasui
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Robison
mesh_terms: D000293:Adolescent; D000328:Adult; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000209:etiology*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D006689:Hodgkin Disease / Q000150:complications* / Q000628:therapy; D006801:Humans; D015994:Incidence; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009017:Morbidity; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D017741:Survivors / Q000706:statistics & numerical data*; D014481:United States / Q000453:epidemiology; D055815:Young Adult