Daniel M Green1, Wei Liu2, William H Kutteh3, Raymond W Ke3, Kyla C Shelton4, Charles A Sklar5, Wassim Chemaitilly6, Ching-Hon Pui7, James L Klosky8, Sheri L Spunt9, Monika L Metzger10, DeoKumar Srivastava2, Kirsten K Ness4, Leslie L Robison4, Melissa M Hudson11. 1. 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. 2. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA. 3. Fertility Associates of Memphis, Memphis, TN, USA; Department of Obstetrics and Gynecology, Vanderbilt University Medical School, Nashville, TN, USA. 4. Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA. 5. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 6. Department of Pediatric Medicine, Division of Endocrinology, St Jude Children's Research Hospital, Memphis, TN, USA. 7. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA. 8. Division of Psychology, St Jude Children's Research Hospital, Memphis, TN, USA. 9. 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. 10. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA. 11. 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.
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. 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.
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.
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