Previous studies investigated the fertility of childhood cancer survivors, frequently in convenience samples, populations with poorly quantified exposures and/or infrequent treatment with those agents most likely to adversely impact fertility such as alkylating agents. The current study provides new information by estimating risk for siring a pregnancy 5 years or more after diagnosis and with specific quantified exposures. The results can inform guideline-based long-term follow-up recommendations.
Compared with the siblings, survivors were approximately half as likely to sire a pregnancy. Byrne et al6
reported that the unadjusted relative risk for fertility was 0.83 (95% CI, 0.74 to 0.93) among the male childhood cancer survivors included in the Five Center Study. This study excluded from the analysis eligible participants who were never married, married before the diagnosis of cancer, had/sired their first pregnancy before the diagnosis of cancer, or who reported no pregnancies and said they did not want children or that they wanted to adopt children. Few participants in the Five Center Study were exposed to gonadotoxic therapies, particularly alkylating agents. In another study of survivors of acute lymphoblastic leukemia, the relative risk for fertility was 0.80 (P
= .47) for survivors who were 18 to 21 years of age when they first sired a pregnancy compared with sibling controls; the relative risk was 1.02 (P
= .93) for survivors who were older than age 21 years at the time they first sired a pregnancy.23
In our treatment models, prior radiation therapy to the testes of more than 7.5 Gy, a summed alkylating agent dose score ≥ 2, treatment with procarbazine, or treatment with higher doses of cyclophosphamide were the major factors that decreased the HR of a CCSS survivor siring a pregnancy. Importantly, those who did not have any of these high-risk exposures were as likely as the siblings to sire a pregnancy.
Previous studies reported that recovery of spermatogenesis was unlikely after single-dose exposures exceeding 4.0 Gy19
or low-dose fractionated exposures.20–22
Loss of both spermatogenesis and androgen secretion occurred at high doses (≥ 24.0 Gy);20–22,24
lower-dose exposures may not produce azoospermia.25,26
Leydig cell function may be preserved when the testicular dose is ≤ 20.0 Gy.27
Severe damage to the testicular germinal epithelium frequently follows treatment which includes an alkylating agent and procarbazine.25,26,28–38
Azoospermia was present in all men by the start of the third cycle of nitrogen mustard, vinblastine, procarbazine, and prednisone chemotherapy.33
Less than 20% had recovery of spermatogenesis when evaluated 37 to 48 months after treatment.32
The chemotherapy regimen originally reported by DeVita et al39
had an AAD score of 6.11
Azoospermia occurred less frequently following treatment with two (AAD score = 2), rather than six (AAD score = 6), cycles of nitrogen mustard, vincristine, procarbazine, and prednisone.38
The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine produced oligo- or azoospermia frequently during the course of treatment, but recovery of spermatogenesis occurred after treatment was completed.34
The administration of cyclophosphamide has been associated with impaired spermatogenesis after treatment of children for nonmalignant40–45
diseases. Azoospermia was reported after cumulative cyclophosphamide doses as low as 6.0 g/m249
whereas spermatogenesis was preserved after cumulative doses as high as 16 g/m2
Impaired spermatogenesis was more likely after cumulative doses exceeding 7.5 to 9.5 g/m2
Cumulative cyclophosphamide doses used in contemporary regimens for Hodgkin's disease (3.2 to 4.8 g/m2
and rhabdomyosarcoma (4.8 to 16.8 g/m2
) (S. Spunt, personal communication, May 2008) correspond to AAD scores of 1 to 3. Current regimens for Ewing sarcoma include cyclophosphamide (8.4 g/m2
) and ifosfamide in combination (63 g/m2
resulting in an AAD score of 6.
Our study demonstrated that young males (0 to 4 years of age at diagnosis) were more likely to sire a pregnancy than those who were 15 to 20 years of age at diagnosis. Some reports suggested that the prepubertal testis was less sensitive than the postpubertal testis to damage by chemotherapy,31,54
but others have questioned this observation.25,48,55–57
This study has a number of strengths. The CCSS is the largest, most thoroughly characterized cohort of survivors of cancer diagnosed during childhood or adolescence. Thus, important questions regarding the frequency of outcomes that may be modified by treatment exposures, as well as the relationship of these exposures to significant, though uncommon, late events can be evaluated with substantial statistical power.
There are also limitations that must be taken into account. The participants were ascertained retrospectively. Fifteen percent of those eligible were lost to follow-up and 16% declined participation. Participants did not differ from nonparticipants with regard to demographic or cancer characteristics.9
Radiation dosimetry was performed using the data supplied by the participating institutions. No independent quality control was performed to determine whether significant data, such as the use of a testicular shield (which can reduce the testicular dose to approximately 1% of the prescription dose),58
The CCSS used self-administered questionnaires for ascertainment of outcomes. Approximately 22% of pregnancies were not recognized clinically.59
Comparison of the number of births reported by NSFG participants 15 to 19 years of age to those ascertained by vital records suggests that 15- to 19-year-old males are not informed of all pregnancies by their partners.10
Information relating to adjustment variables (eg, education and so on) was derived from a single point in time (ie, at baseline questionnaire), was a surrogate for the presence or absence of particular factors at the time of pregnancy, and did not directly measure their influence over time.
We did not evaluate fertility in light of personal choices made by the male CCSS survivors. Some may have chosen not to attempt to sire a pregnancy because they were concerned that they might transmit a trait that would predispose their children to cancer.2
Others may have thought or been told that they were or might be infertile. Factors that may influence their ability to form or maintain an intimate heterosexual relationship include appearance, sexual preference, and neurocognitive function.2,3,60,61
Some of these factors may be related to the therapeutic exposures considered in this analysis and may have confounded the results of our study. Our finding that the HR for siring a pregnancy was not significantly decreased in CCSS participants who experienced none of the high-risk exposures for decreased fertility suggests that these factors may not influence decisions regarding paternity significantly in this group.
We demonstrated that the fertility of male childhood cancer survivors is impaired. Men age 15 to 44 years, who received a testicular radiation dose of more than 7.5 Gy, were treated with procarbazine or cyclophosphamide, or had a summed alkylating agent dose score of ≥ 2, or were less likely to sire a pregnancy. Men diagnosed in early childhood were more likely to sire a pregnancy than those diagnosed in adolescence. These data may be used to counsel patients and their parents before initiation of treatment regarding their future fertility.