Purpose: Radiation has many potential long-term effects on cancer survivors. Female cancer patients may experience decreased fertility depending on the site irradiated. Oncologists should be aware of these consequences and discuss options for fertility preservation before initiating therapy. Methods and Materials: A comprehensive review of the existing literature was conducted. Studies reporting the outcomes for female patients treated with cranio-spinal, abdominal, or pelvic radiation reporting fertility, pregnancy, or neonatal-related outcomes were reviewed. Results: Cranio-spinal irradiation elicited significant hormonal changes in women that affected their ability to become pregnant later in life. Women treated with abdomino-pelvic radiation have an increased rate of uterine dysfunction leading to miscarriage, preterm labor, low birth weight, and placental abnormalities. Early menopause results from low-dose ovarian radiation. Ovarian transposition may decrease the rates of ovarian dysfunction. Conclusions: There is a dose-dependent relationship between ovarian radiation therapy (RT) and premature menopause. Patients treated with RT must be aware of the impact of treatment on fertility and explore appropriate options.

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Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients

Each year more than 20,000 children and young persons of reproductive age are exposed to known mutagens in the form of chemo- and/or radiotherapy for cancer in the States. As more of these treatments are effective there is growing concern that genetic defects are introduced in the germ cells of these young patients. It is well documented for male rodents that treatment with chemo- and radio-therapeutic agents before mating can cause genetic damage in the germ line, and the magnitude of heritable effects depends on the spermatogenic cell stage treated. Similar germinal effects are suspected to occur in humans but remain unproven. Hodgkin's disease (HD) is an example of a malignancy which is typically diagnosed during a patient's reproductive years. In our study we observed eight male HD patients who were treated with NOVP (Novanthrone, Oncovin, Vinblastine, Prednisone) chemotherapy. We evaluated sperm aneuploidy using multi-colour fluorescence in situ hybridization (FISH), and found approximately 5-fold increases in sperm with disomies, diploidies and complex genotypes involving chromosome X, Y and 8. Increases in sex chromosome aneuploidies arose from segregation errors at meiosis I as well as meiosis II. The aneuploidy effects were transient, however, declining to pretreatment levels within approximately 100 days after the end of the therapy. When compared with normal men, some HD patients showed higher proportions of certain sperm aneuploidy types even before their first therapy.

Chemotherapy induces transient sex chromosomal and autosomal aneuploidy in human sperm.

This study was conducted to determine the risk of menopause and infertility in female childhood cancer survivors who received abdominal-pelvic radiation and/or chemotherapy with alkylating agents in comparison with those who were treated by nonsterilizing surgery only. Females who were diagnosed in 1964-1988 before age 20 years with a histologically confirmed malignancy and who had survived for at least 5 years, had attained age 18, and were alive at time of study were identified through the Ontario Cancer Registry. Reproductive outcomes were ascertained by a telephone-administered questionnaire, and treatment data were abstracted from medical records for 830 subjects aged 18-49 years; 719 survivors who were nonmenopausal at the end of treatment were included in the analyses. Survivors who received both alkylating agents and abdominal-pelvic radiation were more likely to be postmenopausal than were those who underwent surgery (risk ratio = 2.58; 95% confidence interval: 1.14, 5.80). Women treated with abdominal-pelvic radiation alone had a fertility deficit of 23% compared with those in the surgery group; the deficit was restricted to women diagnosed postpuberty. Risks of menopause and infertility increased with increasing dose of abdominal-pelvic radiation and amount of alkylating agent.

Early Menopause and Infertility in Females after Treatment for Childhood Cancer Diagnosed in 1964–1988 in Ontario, Canada

Biology and treatment of acute lymphoblastic leukemia

Background

By the year 2010, 1/250 young adults will be long-term survivors of childhood cancer. One of the major concerns is whether they will be able to have healthy children.



Procedure

The literature was reviewed to determine 1) the extent of intrapartum and perinatal complications experienced by survivors or their spouses and 2) the risk of congenital malformations or cancer in their children.



Results and Conclusions

Series have reported on pregnancy complications among approximately 400 female survivors and 300 partners of male survivors. An increased incidence of spontaneous abortions, low-birth-weight babies, and neonatal deaths has been described for women with Wilms tumor who had received at least 20 Gy abdominal radiation. Hodgkin disease survivors who had received both radiation and chemotherapy (but not either alone) also appear to be at increased risk of spontaneous abortions. Based on several thousand survivor offspring, there is no overall increased risk of either congenital malformations or childhood cancer. Further studies will define the outcome of offspring of cancer survivors treated in the modern era. Med. Pediatr. Oncol. 33:29–33, 1999. © 1999 Wiley-Liss, Inc.

Pregnancy outcome in long-term survivors of childhood cancer.

Of all children diagnosed with leukemia in Denmark, Finland, Iceland, Norway, and Sweden, 981 had discontinued therapy before 1985 and had been followed up annually after cessation of therapy. Progeny was registered and fertility evaluated among survivors who passed age 18 years without a relapse (n = 299).



By April 1989, 48 offspring were registered, one of whom had congenital anomalies. This was no more than expected from the incidence of birth defects in the general population. No childhood malignancies or genetic diseases have so far been diagnosed in the progeny, in the study group, none of the 19 female and 8 male survivors of myeloid leukemias had become parents, and only 4 fathers were reported among the 131 male survivors of acute lymphoblastic leukemia (ALL). However, 23 of the 149 females treated for ALL had delivered 41 children. Fertility was measured as cumulative rates of first birth by maternal age. In a Cox regression analysis, cases who had received prophylactic radiation of the central nervous system (CNS) had a lower first birth rate than those without radiation (rate ratio 0.39, 95% CI 0.15–1.00), indicating that doses of 18–24 Gy to the brain may possibly be a risk factor. By using the Norwegian birth cohort of 1966 as a control group, matching the median year of birth for the study subjects, the group of female ALL survivors as a whole was as likely as the general female population to have given birth up to the age of 23.



The first generation of females successfully treated for childhood ALL seems to have a nearly normal reproductive pattern during young adulthood, without increased risk of congenital anomalies in the offspring. However, cranial radiation as CNS prophy laxis may possibly impair subsequent reproduction.

Ruth Wegelius

Papers

Reproduction following treatment for childhood leukemia : a population-based prospective cohort study of fertility and offspring