title: Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study.
abstract: BACKGROUND
  Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer.
  
  
  METHODS
  We did semen analysis on 214 adult male survivors of childhood cancer (median age 7·7 years [range 0·01-20·3] at diagnosis, 29·0 years [18·4-56·1] at assessment, and a median of 21·0 years [10·5-41·6] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling.
  
  
  RESULTS
  Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration ≥15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m(2) were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=-0·37, p<0·0001). Mean CED was 10 830 mg/m(2) (SD 7274) in patients with azoospermia, 8480 mg/m(2) (4264) in patients with oligospermia, and 6626 mg/m(2) (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m(2) CED for azoospermia (OR 1·22, 95% CI 1·11-1·34), and for oligospermia (1·14, 1·04-1·25), but age at diagnosis and age at assessment were not.
  
  
  CONCLUSIONS
  Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m(2). Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services.
  
  
  BACKGROUND
  US National Cancer Institute, American Lebanese Syrian Associated Charities.
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA. Electronic address: daniel.green@stjude.org.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Green
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Fertility Associates of Memphis, Memphis, TN, USA; Department of Obstetrics and Gynecology, Vanderbilt University Medical School, Nashville, TN, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Kutteh
authors.affiliation: Fertility Associates of Memphis, Memphis, TN, USA; Department of Obstetrics and Gynecology, Vanderbilt University Medical School, Nashville, TN, USA.
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Ke
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Kyla C
authors.initials: KC
authors.lastname: Shelton
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Sklar
authors.affiliation: Department of Pediatric Medicine, Division of Endocrinology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Wassim
authors.initials: W
authors.lastname: Chemaitilly
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Division of Psychology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Klosky
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Spunt
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA.
authors.forename: Monika L
authors.initials: ML
authors.lastname: Metzger
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: DeoKumar
authors.initials: D
authors.lastname: Srivastava
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 Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Robison
authors.affiliation: Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Hudson
mesh_terms: D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000627:therapeutic use; D002173:Cancer Care Facilities; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016001:Confidence Intervals; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D059247:Fertility Preservation; D006776:Hospitals, Pediatric; D006801:Humans; D015994:Incidence; D007248:Infertility, Male / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016017:Odds Ratio; D012189:Retrospective Studies; D018570:Risk Assessment; D055101:Semen Analysis; D013076:Sperm Count / Q000379:methods*; D017741:Survivors; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide