Elsevier

The Lancet Oncology

Volume 15, Issue 11, October 2014, Pages 1215-1223
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(14)70408-5Get rights and content

Summary

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/m2 were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=–0·37, p<0·0001). Mean CED was 10 830 mg/m2 (SD 7274) in patients with azoospermia, 8480 mg/m2 (4264) in patients with oligospermia, and 6626 mg/m2 (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m2 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/m2. 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.

Introduction

The treatment of children and adolescents with cancer has become increasingly successful, with about 80% of patients surviving 5 years or more after diagnosis.1 Irradiation of the testes or treatment with certain classes of chemotherapeutic agents, especially alkylating agents, might impair fertility,2, 3 a risk that increases with cumulative doses of alkylating agents, as estimated by the cyclophosphamide equivalent dose (CED).4 Published work about the relation between cumulative alkylating agent exposure and semen variables in adult survivors of childhood cancer is scarce, and often confounded by radiation exposure to the testes or hypothalamic–pituitary axis. We undertook the present study to investigate the independent role of alkylating agent exposure to test the hypothesis that increased exposure 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.

Section snippets

Study design and participants

Our analysis used data available as of April 30, 2013, for male participants in the St Jude Lifetime Cohort Study (SJLIFE) diagnosed and treated for cancer between 1970 and 2002. The continuing SJLIFE5, 6 study includes patients 0–28 years of age at diagnosis who meet the following criteria: diagnosis of childhood malignancy treated at St Jude Children's Research Hospital; survival for 10 years or more from diagnosis; and a present age 18 years or older. SJLIFE participants undergo risk-based

Results

Of 2400 males eligible for the SJLIFE study as of April 30, 2013, 1851 were excluded from the present analysis because of a history of any radiation treatment, no alkylating agent exposure, vasectomy, or present use of androgens. No patient underwent bilteral orchiectomy. Of the 549 men eligible for the semen analysis project, 226 (41%) participated in a SJLIFE on-campus assessment and agreed to semen analysis. 12 were unable to produce a semen specimen, resulting in 214 assessable participants

Discussion

Alkylating agents interfere with spermatogenesis, but there are few data for the effect of host and treatment factors on this risk in survivors of childhood cancer. Using the SJLIFE study, which includes a large cohort of well-characterised, unirradiated male survivors of childhood cancer, we show a correlation between increasing CED and the prevalence of azoospermia (panel). Although impaired spermatogenesis was less likely when the CED was less than 4000 mg/m2, we did not identify a

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