Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study

Lancet Oncol. 2014 Oct;15(11):1215-23. doi: 10.1016/S1470-2045(14)70408-5. Epub 2014 Sep 16.


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.

Findings: 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.

Interpretation: 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.

Funding: US National Cancer Institute, American Lebanese Syrian Associated Charities.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Agents, Alkylating / adverse effects*
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Cancer Care Facilities
  • Child
  • Child, Preschool
  • Cohort Studies
  • Confidence Intervals
  • Cyclophosphamide / adverse effects*
  • Cyclophosphamide / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Fertility Preservation
  • Hospitals, Pediatric
  • Humans
  • Incidence
  • Infertility, Male / chemically induced*
  • Infertility, Male / epidemiology
  • Male
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Odds Ratio
  • Retrospective Studies
  • Risk Assessment
  • Semen Analysis
  • Sperm Count / methods*
  • Survivors
  • Young Adult


  • Antineoplastic Agents, Alkylating
  • Cyclophosphamide