Pediatr Blood Cancer 2004;42:364–372 Fertility of Long-Term Male Survivors of Acute Lymphoblastic Leukemia Diagnosed During Childhood { Julianne Byrne, PhD, 1 * Thomas R. Fears, PhD, 2 James L. Mills, MD, MS, 2 Lonnie K. Zeltzer, MD, 3 Charles Sklar, MD, 4 Anna T. Meadows, MD, 5 Gregory H. Reaman, MD, 1 and Leslie L. Robison, PhD 6 INTRODUCTION Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. In the United States during the years 1990 – 1995, ALL constituted 18.5% of all newly diagnosed cancers in young people aged less than 20 [1]. As the continuing success of modern cancer treatment has raised 5-year relative survival for ALL to 77% [1], the lasting consequences of therapy on the every- day life of survivors become more important. Among the chief concerns of cancer survivors are the maintenance of fertility and the possibility of starting a family. There is growing realization that fertility impair- ments arise from certain specific types of therapies and are present only in subgroups of survivors. Leukemia typically occurs early in childhood; long-term effects of current therapies on fertility cannot be evaluated for many years until survivors reach their reproductive years. As newer and more aggressive therapies come into use, continued long-term follow-up studies of large numbers of survivors are needed to tease out the effects of specific therapies on subgroups. Treatment-related fertility deficits have been shown in retrospective cohort studies of survivors of the most common types of childhood cancer [2], but because of their young age at diagnosis leukemia survivors were not represented in large numbers in these studies. Thus, little is known of the effects on their fertility of treatments received by ALL survivors. In order to evaluate proven fertility among men who had survived leukemia diagnosed during childhood or adolescence, the National Institutes of Health collaborated with the Children’s Cancer Group (CCG, since subsumed into the Children’s Oncology Fertility impairments among men treated during childhood for cancer are known to occur after some, but not all, types of anti-cancer therapy. This is the first study to evaluate proven fertility among adult male survivors of child- hood acute lymphoblastic leukemia (ALL). In a retrospective cohort study, proven fertility (ever fathered a pregnancy) was evaluated by self- report among 213 men treated for ALL before age 18 on protocols of the Children’s Cancer Group (CCG). Controls (N ¼ 145) were drawn from among male siblings. Overall, with a pro- portional hazards analysis, proven fertility of male survivors was not different from that of controls (relative fertility (RF) ¼ 0.95, 95% CI 0.63–1.43). However, married men treated before age 10 with high dose (24 cGy) cranial radiotherapy (RT), without spinal RT, had only 9% of the fertility of controls (Relative risk, RR ¼ 0.09, 95% CI 0.01–0.82). High dose cranial RT at older ages was not associated with a statistically significant fertility deficit (RR ¼ 0.56, 95% CI 0.25–1.28). In this first study of proven fertility among men treated for childhood leukemia, the majority of survivors showed no evidence of fertility impairment compared to controls. However, men treated at a young age with high dose cranial RT may have impaired fertility. These results suggest that further investigation of men with these treat- ments is needed to confirm and extend these findings. Pediatr Blood Cancer 2004;42:364– 372. ß 2003 Wiley-Liss, Inc. Key words: cohort study; fertility; male childhood leukemia survivors; radiotherapy —————— 1 The Children’s National Medical Center, Washington, DC 2 The National Institutes of Health, Bethesda, Maryland & Department of Health and Human Services, Washington, DC 3 The Children’s Cancer Group, Arcadia, California, University of California at Los Angeles, Los Angeles 4 Memorial-Sloan Kettering Cancer Center, New York 5 Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 6 The University of Minnesota Cancer Center, Minneapolis, Minnesota { This manuscript was originally submitted to and accepted for publication in Medical & Pediatric Oncology by its Editor-in-Chief, Dr. G. D’Angio. This study was designed and implemented by the National Cancer Institute (NCI) and the National Institute of Child Health and Human Development, NIH, while Dr. Byrne was an NCI staff member. *Correspondence to: Julianne Byrne, Department of Hematology/ Oncology, Children’s National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010. E-mail: jbyrne@cnmc.org Received 6 July 2003; Accepted 18 July 2003 ß 2003 Wiley-Liss, Inc. DOI 10.1002/pbc.10449