Janis C. Kelly

June 06, 2014

CHICAGO — Nearly half of all male long-term survivors of childhood cancer who were treated with alkylating agents had normal sperm counts 20 years after treatment, but the rest were likely to have reduced sperm counts, new research shows.

"Our key finding was that there really is no uniformly 'safe' or 'toxic' alkylating agent dose threshold with regard to toxicity to sperm, although most of those treated with less than 4000 mg/m² were normospermic," said investigator Daniel M. Green, MD, from the Department of Epidemiology and Cancer Control and the Department of Oncology at St. Jude Children's Research Hospital in Memphis, Tennessee.

Options for preserving fertility in males facing treatment for childhood cancer are limited. For those who are postpubertal, semen cryopreservation is a possibility. "For those who are prepubertal, all techniques available are, at the present time, experimental," he told Medscape Medical News.

"I was surprised at the substantial overlap of cumulative doses among the normospermic, oligospermic, and azoospermic participants. This suggests that factors other than cumulative drug dose are important in determining chemotherapy toxicity to spermatogenesis," Dr. Green said.

One important factor might be genetic variation in drug-metabolizing pathways. It is possible that unidentified genes influence spermatogenesis and that other drugs (including platinating agents) interact with the classical alkylating agents. "We did try to examine this and found no evidence of an effect, but the number of available participants exposed to both was small," he reported.

Dr. Green and his colleagues used data from the St. Jude Lifetime (SJLIFE) Cohort Study to examine the relation between cyclophosphamide equivalent dose (CED) of alkylating agents and sperm count.

They evaluated 214 men who were long-term survivors of childhood cancer and who had not been treated with radiation therapy. The mean age of the men was 29.8 years and the mean time since cancer diagnosis was 21.6 years.

A sperm concentration of 0 was defined as azoospermia, below 15 million/mL was defined as oligospermia, and above 15 million/mL was defined as normospermia.

Table. Outcome by Dose of Alkylating Agent

CED (mg/m²) Azoospermia, % Oligospermia, % Normospermia, %
<4000 2.9 8.6 86.6
4000 to 8000 23.2 32.9 43.9
>8000 34.0 29.9 36.1

 

Multinomial logistic regression analysis, adjusted for age at diagnosis and at follow-up, demonstrated that for each 1000 mg/m² increase in alkylating agent exposure beyond 4000 mg/m², the risk for oligospermia increased about 14% and the risk for azoospermia increased about 22%.

However, Dr. Green emphasized that there was a wide distribution of sperm counts over the range of CED doses.

He explained that 200 of the 214 patients received cyclophosphamide, so the researchers were not able to look at individual doses of different drugs to determine whether any specific alkylators are safer, in terms of spermatotoxicity, than others.

"This study adds to our understanding of alkylating agents in childhood cancer by providing very good data regarding the impact of cumulative dose on outcome," Dr. Green pointed out. "Previous studies were either too small to do this or did not look at dose as a variable, other than using predetermined cumulative doses that were stated to be 'sterilizing'," he explained.

Dr. Green has disclosed no relevant financial relationships.

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO). Abstract 10010. Presented June 1, 2014.

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