Julianne Byrne

Fertility of female survivors of childhood cancer: A report from the childhood cancer survivor study

PURPOSE This study was undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on fertility. PATIENTS AND METHODS We reviewed the fertility of female participants in the Childhood Cancer Survivor Study (CCSS), which consisted of 5-year survivors, and a cohort of randomly selected siblings who responded to a questionnaire. Medical records of all members of the cohort were abstracted to obtain chemotherapeutic agents administered; the cumulative dose of drug administered for several drugs of interest; and the doses, volumes, and dates of administration of all radiation therapy. RESULTS There were 5,149 female CCSS participants, and there were 1,441 female siblings of CCSS participants who were age 15 to 44 years. The relative risk (RR) for survivors of ever being pregnant was 0.81 (95% CI, 0.73 to 0.90; P < .001) compared with female siblings. In multivariate models among survivors only, those who received a hypothalamic/pituitary radiation dose > or = 30 Gy (RR, 0.61; 95% CI, 0.44 to 0.83) or an ovarian/uterine radiation dose greater than 5 Gy were less likely to have ever been pregnant (RR, 0.56 for 5 to 10 Gy; 95% CI, 0.37 to 0.85; RR, 0.18 for > 10 Gy; 95% CI, 0.13 to 0.26). Those with a summed alkylating agent dose (AAD) score of three or four or who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant. CONCLUSION This large study demonstrated that fertility is decreased among female CCSS participants. The risk factors identified may be utilized for pretreatment counseling of patients and their parents.

Fertility of Male Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study

PURPOSE This study was undertaken to determine the effect of treatment for childhood cancer on male fertility. PATIENTS AND METHODS We reviewed the fertility of male Childhood Cancer Survivor Study survivor and sibling cohorts who completed a questionnaire. We abstracted the chemotherapeutic agents administered, the cumulative dose of drug administered for selected drugs, and the doses and volumes of all radiation therapy from medical records. Risk factors for siring a pregnancy were evaluated using Cox proportional hazards models. RESULTS The 6,224 survivors age 15 to 44 years who were not surgically sterile were less likely to sire a pregnancy than siblings (hazard ratio [HR], 0.56; 95% CI, -0.49 to 0.63). Among survivors, the HR of siring a pregnancy was decreased by radiation therapy of more than 7.5 Gy to the testes (HR, 0.12; 95% CI, -0.02 to 0.64), higher cumulative alkylating agent dose (AAD) score or treatment with cyclophosphamide (third tertile HR, 0.42; 95% CI, -0.31 to 0.57) or procarbazine (second tertile HR, 0.48; 95% CI, -0.26 to 0.87; third tertile HR, 0.17; 95% CI, -0.07 to 0.41). Compared with siblings, the HR for ever siring a pregnancy for survivors who had an AAD score = 0, a hypothalamic/pituitary radiation dose = 0 Gy, and a testes radiation dose = 0 Gy was 0.91 (95% CI, 0.73 to 1.14; P = .41). CONCLUSION This large study identified risk factors for decreased fertility that may be used for counseling male cancer patients.

Quality of life in long-term survivors of CNS tumors of childhood and adolescence.

Clinical reports of small numbers of pediatric brain tumor patients observed for brief periods suggest that long-term survivors continue to have major handicaps into adulthood. To quantify these late effects we interviewed 342 adults (or their proxies) who had CNS tumors diagnosed before the age of 20 between 1945 and 1974, survived at least 5 years, and reached 21 years of age. Survivors were 32 years old on average at follow-up. When compared with 479 matched siblings as controls. CNS tumor survivors were more likely to have died or to have become mentally incompetent sometime during the follow-up period. They were more likely to be at risk for such adverse outcomes as unemployment (odds ratio [OR], 10.8; 95% confidence interval [CI], 4.6 to 25.7], to have a health condition that affected their ability to work (OR, 5.9; CI, 3.7 to 9.4), to be unable to drive (OR, 28.8; CI, 6.9 to 119.9), or to describe their current health as poor (OR, 7.8; CI, 1.7 to 35.7). Unfavorable outcomes were more frequent in male survivors than in females, in those with supratentorial tumors compared with infratentorial ones, and in those who received radiation therapy. As clinicians consider improving therapies, they should anticipate late effects, such as those we observed, and attempt to target subgroups for interventions that may improve subsequent quality of life.

Fertility and pregnancy after treatment for cancer during childhood or adolescence

Because most children and adolescents with cancer now survive, issues regarding the late effects of therapy, including fertility and the health of offspring, are increasingly important. This article summarizes the literature regarding issues related to fertility in survivors of cancer, including actual fertility, gonadal function, menarche, menopause, and birth defects and cancer in the offspring.

Prevalence of müllerian duct anomalies detected at ultrasound

The true prevalence of müllerian duct abnormalities is not well established. We used standard ultrasound examinations to establish the prevalence of müllerian duct abnormalities in girls and women who were evaluated for reasons unrelated to the presence of uterine anomalies. Prospective ultrasound examinations for nonobstetric indications in 2,065 consecutive girls and women (aged 8-93) showed that 8 had anomalies, including bicornuate uterus, septate uterus, and double uterus. In this first attempt to determine the prevalence of uterine anomalies in the general population, using noninvasive methodology, the rate of anomalies was 3.87 per 1,000 women (exact 95% confidence interval: 1.67-7.62), or approximately 1 in 250 women. This prevalence estimate may be greater than the true rate if selection biases are strong, or less than the true prevalence if ultrasound detection rates are low. As a first attempt to establish the prevalence by pelvic ultrasound in a consecutive series, these data may serve as a baseline estimate.

Prognostic factors and secondary malignancies in childhood medulloblastoma

Purpose Little is known of the outcome of long-term survivors of childhood medulloblastoma, one of the most common pediatric malignancies. To determine the potential for secondary malignancies, a retrospective outcome evaluation in 88 consecutive cases of childhood medulloblastoma was performed. Patients and Methods The records of all patients with childhood medulloblastoma diagnosed at Childrens National Medical Center in Washington, DC from 1969 through 1997 were reviewed. Results The median follow-up time was 92 months (range 6–257 months). Overall survival was 59% at 5 years and 52% at 10 years. Univariate analysis showed that age at diagnosis, extent of surgical resection, presence of metastatic disease (M stage), ventriculoperitoneal shunt placement within 30 days from diagnosis, posterior fossa radiation therapy dose, and adjuvant chemotherapy significantly affected survival. Although based on small numbers, the risk of second neoplasms was significantly increased in this cohort. Multiple basal cell carcinomas developed in the areas of radiation therapy in two patients; these patients also had nevoid basal cell carcinoma syndrome (NBCCS) diagnosed. One other patient died of glioblastoma multiforme 8 years after treatment of medulloblastoma. A meningioma developed in another patient 10 years after radiation therapy. Conclusion As survival of medulloblastoma patients improves, increased surveillance regarding secondary malignancies is required, especially because radiation-induced tumors may occur many years after treatment. These two cases of NBCCS also illustrate the importance of considering the concomitant diagnosis of NBCCS in young patients with medulloblastoma. In those patients, alternative therapy should be considered to minimize radiation therapy-related sequelae.

Death during adulthood in survivors of childhood and adolescent cancer

Background. Therapeutic advances have extended survival for most children and adolescents with cancer beyond 5 years from diagnosis. However, excess mortality continues beyond 5 years, and a significant portion results from causes other than the primary cancer. Risk factors for these deaths are not currently known. Thus, the authors studied mortality in a cohort of adult survivors of childhood and adolescent cancer to determine whether survivor characteristics were associated with increased relative risk of death from other causes.

Long-term genetic and reproductive effects of ionizing radiation and chemotherapeutic agents on cancer patients and their offspring

The continuing search for a cure for cancer has lead to more aggressive therapies as new agents are developed with largely unknown late complications. Standard therapy for the majority of cancers today, following surgery, often consists of combinations of high doses of radiation and multi-drug therapy. Compared with exposures experienced by atomic bomb survivors, cancer survivors have been exposed to higher doses of partial body irradiation and combination chemotherapy over longer periods. Thus, cancer survivors provide a model system with which to evaluate the long-term effects on the human organism of high doses of agents known to damage DNA. Five-year survival after cancer diagnosis is now greater than 56%; more than 5 million Americans are considered cured of cancer. However, the late complications of cancer in long-term survivors has been poorly evaluated, especially in adults, and little is known of the most troubling possibility, that is, that the effects of cancer treatments could be passed on to the next generation. What little we know comes from studies of at most 5,000 survivors of childhood cancer, treated decades ago. So far, results are reassuring that with the means now available, we cannot detect clinical evidence of heritable damage. However, reproductive effects, including infertility, are common consequences of cancer therapy and may represent germ cell damage. We are just in the infancy of studies of germ cell mutagenesis in cancer survivors. The relatively small numbers of survivors, and the few types of exposures studied so far, provide only limited grounds for reassurance. More comprehensive, properly designed, studies of modern new agents are urgently need.

Genetic Disease in Offspring of Long-Term Survivors of Childhood and Adolescent Cancer Treated with Potentially Mutagenic Therapies

To the Editor:​Editor: Table 1 Sex of Offspring of Cancer Survivors (Stratified by Type of Treatment Received) and of Sibling Controls With increasing survival to reproductive age among individuals treated during childhood or adolescence by anticancer regimens that included mutagenic agents—and, in many cases, with recovery of fertility—there is concern that germ cells may carry mutations that could lead to genetic disease in offspring. A large body of evidence suggests that radiation and alkylating agents are mutagenic toward germ cells (Witt and Bishop 1996). However, numerous studies evaluating genetic disease among offspring of individuals who previously received therapy for cancer with radiation or chemotherapy have not found evidence of significant increases in such genetic disease in the offspring (Byrne et al. 1998). Nevertheless, the following questions remain: What is the upper confidence limit of the level of genetic disease that might have been induced but remained undetected? How can the information available be used in combination with future studies, with the goals of either detecting genetic disease or further lowering this upper confidence limit? In the largest study of genetic disease among offspring of cancer survivors (Byrne et al. 1998), 2,198 offspring of 1,062 long-term survivors of childhood cancer and 4,544 offspring of 2,032 sibling controls were studied. Most of the data were analyzed to compare the 2,198 offspring of the overall group of cancer survivors with those of the sibling control group. However, only 235 of the 1,062 cancer survivors received “potentially mutagenic therapy,” defined as either radiotherapy below the diaphragm and above the knee or chemotherapy with an alkylating agent. The 408 offspring of these 235 survivors constitute the group most likely to be at risk for genetic disease, since the other 1,790 offspring were born to parents who received treatment that would be expected either to be nonmutagenic or to have a low mutagenic potential. We thought it essential for proper interpretation of the results of this study, as well as for combining these data with the results of other studies, to separately report all of the data on genetic disease in the offspring, according to the mutagenic potential of the therapy received by their parents, which was not done in the original report (Byrne et al. 1998). Furthermore, since mechanisms of mutation induction differ by sex—because different germ cells are at risk—we have also stratified the data by the sex of the exposed survivor, which was not done consistently in the original study. Table 1 presents the numbers of survivors and their offspring, stratified as described above. There were no significant differences between the male-to-female sex ratios among the offspring of the group treated with potentially mutagenic therapy and any of the control groups (the survivors treated with nonmutagenic therapy, the siblings of the survivors, or the combination of these two groups). However, when these data are combined with the second largest study of offspring of survivors of childhood cancer, which involved 161 offspring of survivors who had received potentially mutagenic therapy (Hawkins 1991), the male-to-female sex ratio among offspring of female survivors who had received potentially mutagenic therapy (0.85) was significantly lower than that for survivors exposed to nonmutagenic therapy (1.09) and, in further support of the result, was lower than that for the general population (1.06) (both P=.05, two-tailed χ2 test). Although this shift is in the expected direction for induction of mutations, since sex-linked lethal mutations on the X chromosomes would selectively reduce the number of male offspring, the statistical significance of the result is marginal; future studies are needed to confirm or refute this observation. Analysis of the incidence of all genetic disease among the offspring (table 2​2)) showed no significant difference between the survivors who had received potentially mutagenic therapy and any of the control groups for male parents, female parents, or both sexes combined (P>.4). The frequency of genetic disease among offspring of women treated with nonmutagenic therapy was marginally higher (P=.045, two-tailed χ2 test) than that among the offspring of sibling controls. Although the marginal statistical significance may be a result of chance, possible biological explanations for this unexpected finding are that some of the nonalkylating agents may be mutagenic or may cause uterine damage, or the higher frequency of uterine anomalies in girls with Wilms tumor (Nicholson et al. 1996) may result in deformations that mimic genetically caused birth defects. Table 2 Genetic Disease among Offspring of Cancer Survivors Treated with Potentially Mutagenic Therapy or with Less- or Nonmutagenic Therapy and among Controls, Stratified by Sex of Parent Who Was a Subject[Note] Table 3 Genetic Disease among Offspring of Cancer Survivors Treated with Potentially Mutagenic Therapy, or with Less- or Nonmutagenic Therapy and among Control Subjects, by Type of Genetic Disease[Note] The data in table 2 were used to determine the minimum percentage increase in incidence of genetic disease among the offspring of survivors treated with potentially mutagenic therapy that, if present, could have been detected with 95% confidence (one-tailed test for comparison of two proportions), because these treatments produce mutations in many other systems), with a power of 80% (Fleiss 1991). This increase was 85% when the control group comprised only the offspring of the siblings and 82% when the control group comprised the offspring of siblings and those exposed to nonmutagenic treatment. Note that these incidences are higher than the 40% increase reported in the original study, because we limited the group at risk to the offspring of survivors who had received potentially mutagenic therapy. Furthermore, when these data are combined with those of the Hawkins study (Hawkins 1991), there is still no evidence of an increase in genetic disease in the offspring of survivors treated with potentially mutagenic therapy, but the upper limit of the possible increase in genetic disease that would have remained undetected is slightly reduced, to 76%. In table 3, the specific types of genetic disease are stratified according to the type of treatment received. There were no significant differences in the frequencies of the individual types of genetic disease between the offspring of survivors treated with potentially mutagenic therapy and those of any of the control groups (P>.3), whether the data were analyzed for the offspring of male and female survivors individually (see footnotes, table 3) or after grouping the offspring of male and female survivors. Thus, this reexamination of the original report (Byrne et al. 1998) failed to detect any significant induction of genetic disease in offspring of survivors treated with potentially mutagenic therapy for childhood cancer, but it raised the upper limit on the percentage increase that can be ruled out. Further studies must be pursued to determine whether there are low levels of induced genetic disease among offspring of patients treated with potentially mutagenic anticancer agents and, if no increases are found, to provide data for meta-analyses to further reduce the level of increase in genetic disease that can be excluded.

Menarche in a cohort of 188 long-term survivors of acute lymphoblastic leukemia

OBJECTIVE As more children survive acute lymphoblastic leukemia (ALL), questions are raised regarding how the disease and its therapy affect their pubertal development. STUDY DESIGN The National Institute of Child Health and Human Development-National Cancer Institute-Childrens Cancer Group Leukemia Follow-Up Study used a historical cohort design to investigate menarche in 188 ALL survivors who were premanarchal at diagnosis, aged at least 18 years, at least 2 years after diagnosis, alive, and in remission. Female siblings of ALL survivors (n = 218) served as control subjects. RESULTS Menarche occurred within the normal age range in 92% of survivors and 96% of the control subjects (p = 0.09). Early menarche occurred in four survivors (2%) and three control subjects (1%). Delayed, absent, or medically induced menarche was reported by 12 survivors (6%) and six control subjects (3%). Compared with the control subjects, survivors of ALL who received 1800 cGy cranial radiation before the age of 8 years had significantly earlier menarche, relative hazard (RH) of 2.2 (95% confidence interval: 1.4, 3.4 [p = 0.0003]). Survivors receiving 2400 cGy of craniospinal radiation with or without abdominal radiation had significantly later menarche than the control subjects, RH 0.4 (95% confidence interval: 0.3, 0.7 [p = 0.0002]). CONCLUSIONS In this large cohort of ALL survivors, the risk of disordered menarche was low. However, younger subjects receiving 1800 cGy cranial radiation and those receiving 2400 cGy below the diaphragm required careful monitoring.