Abstract
Purpose
Improved treatment for childhood cancer has led to better survival rates of 83 % today. However, long-term side effects including infertility of pediatric patients receiving oncologic treatment remain unclear. We examined the association of chemotherapy and radiotherapy with infertility in survivors of pediatric cancer.
Methods
A questionnaire on fertility was sent to adult survivors listed in the German Childhood Cancer Registry. Fertility status was defined based on information on attempts to conceive, pregnancies, births, menstrual cycle and previous fertility test results.
Results
Therapeutic data were obtained from treatment optimization trials. We included 618 childhood cancer survivors (384 women) who reported information allowing us to classify their current fertility status as ‘fertile/probably fertile’ or ‘probably infertile’. Thirty-one percent of 83 female and 29 % of 117 male survivors reported infertility based on previous fertility tests. ‘Probably infertile’ adult survivors were more likely to have received pelvic radiotherapy (women: adjusted OR 20.24, 95 % CI 4.69–87.29; men: 12.22; 1.18–126.70) than those who were ‘fertile/probably fertile’. Etoposide, particularly ≥5,000 mg/m2 in women, and carboplatin and/or cisplatin in both sexes seemed to have independent risk potential for infertility. Similarly, cancer treatment during or post-puberty compared to treatment before puberty showed a trend toward increased infertility, particularly in male survivors.
Conclusions
Patients and families need to be informed about fertility-preserving measures prior to and also after chemotherapy and radiotherapy.
Keywords: Fertility, Pediatric oncology, Chemotherapy, Radiotherapy, Gonadotoxicity, Risk factors
Background
After successful treatment, childhood cancer survivors still have an elevated risk for late effects, such as a possible impairment of fertility. While the rate of infertility among couples of the German general population is approximately 5 % (Gnoth et al. 2005; Ochsendorf 1996), the infertility rate in individuals who have undergone cancer therapy during childhood appears to be considerably higher (Green et al. 2009, 2010; Byrne et al. 1987; Reulen et al. 2009; Balcerek et al. 2012). Therefore, childhood cancer survivors are found to be less likely of ever parenting a child (Madanat et al. 2008; Pivetta et al. 2011; Hohmann et al. 2011). Impaired fertility may be caused by oncological treatment procedures such as radiotherapy in the genital area (Wallace et al. 1989; Green et al. 2009; Byrne et al. 1987) or certain chemotherapeutic drugs, especially alkylating agents, such as procarbazine in boys (Bogdanovic et al. 1990; Mackie et al. 1996; Green et al. 2010) or cyclophosphamide, which has been used frequently in the treatment for childhood cancer (Schmidt et al. 2010; Green et al. 2010). Several small studies suggested that apart from radiation treatment, the following eight drugs may dose dependently lead to impaired fertility: busulfan, carboplatin, cisplatin, cyclophosphamide, etoposide, ifosfamide, melphalan and procarbazine (Meistrich et al. 2005; Clemm et al. 2003; Gerres et al. 1998).
In order to improve the treatment and survival rate of children suffering from malignant diseases, the German Society for Pediatric Oncology and Hematology (GPOH) has been carrying out nationwide treatment optimization trials for various kinds of oncological diseases since the mid-seventies. These clinical trials include 90 % of all German children with oncological diseases, i.e., they have received a protocol-based therapy (Weber et al. 2001). We found that protocols of treatment optimization trials for patients with Ewing’s sarcoma, non-Hodgkin lymphoma, Hodgkin’s lymphoma, low-grade glioma, nephroblastoma, neuroblastoma, osteosarcoma and soft tissue sarcoma have included at least one of the eight agents mentioned above at accumulated dosages that may lead to infertility.
For several treatment elements in the above-mentioned therapy protocols, little is known about a dose-dependent effect on fertility impairment in girls and boys after treatment for a malignant disease.
Objectives
The primary objective of the present analysis was to examine the association of different chemotherapeutic agents and radiotherapy as part of childhood cancer treatment with infertility in adults who survived pediatric cancer.
Methods
Study design and setting
A pilot survey on having children after surviving cancer in childhood or adolescence was carried out among former patients in Berlin in 2006 (Reinmuth et al. 2008). In collaboration with the German Childhood Cancer Registry (GCCR), which has been collecting data since 1980, we conducted the first nationwide survey ‘Fertility after Chemotherapy and Radiotherapy in Childhood and Adolescence, FeCt’ from April 2008 to February 2009 among German survivors of almost all entities of cancer in childhood or adolescence.
Data assessment
The GCCR database included information about the kind and date of diagnosis and birth dates of participants. The GCCR sent former patients a four-page questionnaire including questions about own children, the wish to have own children, menstrual cycle, attempts to conceive, pregnancies and their courses, the health status of the participants’ children and results of previous fertility tests. On the basis of the questionnaire data, the patients were classified as ‘fertile/probably fertile’ or ‘probably infertile’ as the main outcome variable (Table 1).
Table 1.
Classification of male (n = 234/618) and female participants (n = 384/618) into the groups ‘fertile/probably fertile’ and ‘probably infertile’ according to the information provided on their questionnaires (WHO (1999), Rowe et al. (2004))
| Women | Men | |
|---|---|---|
| Fertile/probably fertile | Child born | Fathered a child |
| Pregnancy | Caused pregnancy | |
| Fertility test normal | Fertility test normal | |
| Probably infertile | No menstruation to date | Tried to father a child unsuccessfully for at least 24 months (if partner not infertile)a |
| No menstruation since therapy | Fertility test result abnormalb | |
| Tried to have a baby unsuccessfully for at least 24 months (if partner not infertile)a | ||
| Fertility test result abnormalc |
aAccording to the WHO definition for infertility (WHO (1999))
bHormone analysis: low estrogen or progesterone level, elevated follicle-stimulating hormone (FSH) or luteinizing hormone (LH) level; result: proven infertility (Wiegratz 2011)
cHormone analysis: low testosterone level, elevated FSH or LH level; sperm analysis: oligozoospermia or azoospermia; result: proven infertility (Rowe et al. (2004))
Information regarding the chemotherapeutic agents and radiotherapy was obtained through different pediatric treatment optimization trials in which the childhood cancer patients were included. The cumulative doses of chemotherapeutic drugs and radiation prescribed in the relevant protocol to be administered to each patient were determined.
Participants
Adult survivors of childhood cancer were eligible for participation if they fulfilled the following inclusion criteria: (1) treated in one of the German oncological centers according to a treatment optimization trial; (2) treated between 1980 and 2004; (3) diagnosed up to their 15th birthday; (4) ≥18 years old at the time of the survey; and (5) written informed consent for the survey. Excluded were patients with Hodgkin’s disease as extensive data on the gonadotoxicity of their treatment protocols were already available from previous studies (Schellong et al. 1999). Patients who had received stem cell transplants were also excluded to avoid their exposure to unnecessary stress since the prevalence of infertility among these patients is known to be particularly high (Sanders et al. 1988; Sarafoglou et al. 1997). Furthermore, we excluded cancer patients with recurrent disease or malignant secondary disease, as the cumulative drug doses in these patients cannot be determined reliably. The study was approved by the Ethical Committee of the Charité University Medical Center Berlin, Germany (July 30, 2002).
In collaboration with the GCCR, 4,564 former patients who had been diagnosed with cancer between 1980 and 2004 were contacted. Sixty percent (n = 2,754) of the 4,564 patients who were contacted participated in the survey (Fig. 1). The distribution of pediatric oncological diagnoses among the study participants was comparable with the distribution of oncological diagnoses among patients who did not respond to the study, based on information of the German Childhood Cancer Registry (Fig. 2).
Fig. 1.
Flowchart showing the inclusion of the FeCt study participants for the current analyses. GCCR German Childhood Cancer Registry, TOT treatment optimization trials
Fig. 2.
Distribution of pediatric oncological diagnoses among former childhood cancer patients who participated in the nationwide survey on fertility in 2008 (n = 2,754) in comparison with the distribution of oncological diagnoses among patients who did not respond to the study (n = 1,810), based on information of the German Childhood Cancer Registry
Statistical methods
The data were analyzed using the Statistical Package for the Social Sciences (SPSS), version 17. Crude odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated separately for women and men using logistic regression analyses to estimate the impact of puberty status (defined by age <13 vs. ≥13 years in males, by menarche in females), chemotherapeutic medications that are suspected of causing infertility (‘etoposide,’ ‘carboplatin and/or cisplatin’ and ‘cyclophosphamide and/or ifosfamide’ each in cumulative doses classified as high or medium exposure vs. none) and radiotherapy protocols (pelvic radiation vs. other or no radiation) on the fertility status. In multivariable analyses with the outcome ‘probably infertile/infertile’ compared to ‘probably fertile/fertile,’ we included the following variables: pelvic radiotherapy, puberty status at diagnosis and treatment with the chemotherapeutic agents such as etoposide, carboplatin and/or cisplatin and ‘cyclophosphamide and/or ifosfamide.’ Participants with missing data were excluded listwise.
Results
For the present analysis on possible risk factors for fertility impairment in adult childhood cancer survivors, we included 618 respondents, 384 women (62.1 %) and 234 men (37.9 %), in the survey who had sufficient information to classify their current fertility status as either ‘fertile/probably fertile’ or ‘infertile/probably infertile’ and available treatment data. The participants included in the present analysis were more likely to be female and slightly older at cancer treatment compared to those participants with insufficient data (Table 2).
Table 2.
Demographic and treatment characteristics of survey participants
| Variable | Total survey participants with former treatment data (n = 2,516) | |
|---|---|---|
| Participants with ascertainable fertility status (n = 618) | Participants without ascertainable fertility status (n = 1,898) | |
| Women | 62.1 % | 50.3 % |
| Median age at survey (range) | 30.0 y (19–43) | 23.0 y (19–43) |
| Median age at cancer diagnosis (range) | 10.0 y (0–15) | 7.0 y (0–15) |
| Median time since cancer diagnosis (range) | 22.0 y (4–28) | 16.0 y (4–28) |
| Pelvic/spinal radiation (yes) | 4.1 % | 3.3 % |
| Cyclophosphamide (yes) | 67.6 % | 61.8 % |
| Ifosfamide (yes) | 19.4 % | 22.6 % |
| Etoposide (yes) | 17.0 % | 18.0 % |
| Carboplatin (yes) | 1.9 % | 1.7 % |
| Cisplatin (yes) | 12.8 % | 14.9 % |
y years
Women
Eighty-six percent (330/384) of the women were classified as ‘fertile/probably fertile’ and 14.1 % (54/384) as ‘probably infertile.’ Thirty-one percent (26/83) of the female participants who had previously undergone a fertility test reported that possible infertility had been diagnosed. Female participants reporting a previous fertility testing received radiotherapy in the pelvic region more often (8.0 %) in comparison with those who did not report previous fertility testing (4.9 %, P = 0.236).
Twenty-six pregnancies were reported by female participants who received cumulative cyclophosphamide doses >5,000 mg/m². Fourteen of these 26 female participants received doses between 10,800 and 23,900 mg/m². Twenty-one female participants became pregnant after receiving doses of ifosfamide > 42,000 mg/m².
The univariate analysis showed that female participants who were treated after menarche had a statistically significant twofold higher risk of being infertile compared to those who had not had their menarche at the time of diagnosis. After adjustment for potential confounders, the odds ratio was still increased, but no longer statistically significant.
Seventeen of 374 (4.5 %) female participants eligible for the multivariable analyses received irradiation of the pelvic region, with an average radiation dose of 37.2 Gray (Gy, range 15–54 Gy). With a 20-fold increased risk, radiotherapy of the pelvic region was the strongest risk factor for infertility in women. There was no association between cyclophosphamide and/or ifosfamide administration and fertility status. For the platinum derivatives group (carboplatin/cisplatin) and etoposide, we found significant associations with increased infertility in the univariate analysis. The likelihood of infertility remained elevated or increased further (in childhood cancer survivors who received high cumulative dosages of etoposide) after adjustment for the other potentially gonadotoxic drugs, radiotherapy and puberty status at diagnosis (Table 3).
Table 3.
Association of probable infertility in women (n = 54/374) with puberty status at diagnosis and exposure to chemotherapy and/or radiotherapy compared to women who are fertile/probable fertile (n = 330/374)
| Univariate | 95 % CI | Adjusted | 95 % CI | |
|---|---|---|---|---|
| OR | P | OR | P | |
| Puberty status at diagnosis | ||||
| Before first period (n = 271) | 1 | – | 1 | – |
| After first period (n = 103) | 2.23 | 1.20 to 4.14 | 1.51 | 0.74 to 3.08 |
| 0.011 | 0.259 | |||
| Cyclophosphamide and/or ifosfamide (mg/m2) | ||||
| None (n = 69) | 1 | – | 1 | – |
| 1–4,999/1–41,999 (n = 248) | 0.63 | 0.31 to 1.28 | 0.74 | 0.31 to 1.75 |
| 0.200 | 0.494 | |||
| ≥5,000/≥42,000 (n = 57) | 0.86 | 0.35 to 2.12 | 0.26 | 0.06 to 1.13 |
| 0.740 | 0.072 | |||
| Carboplatin and/or cisplatin (mg/m2) | ||||
| None (n = 320) | 1 | – | 1 | – |
| 1–1,999/1–499 (n = 37) | 2.69 | 1.18 to 6.16 | 1.56 | 0.58 to 4.22 |
| 0.019 | 0.378 | |||
| ≥2,000/≥500 (n = 17) | 9.30 | 3.54 to 24.45 | 2.93 | 0.73 to 11.69 |
| 0.000 | 0.128 | |||
| Etoposide (mg/m2) | ||||
| None (n = 303) | 1 | – | 1 | – |
| 1–4,999 (n = 65) | 3.44 | 1.80 to 6.55 | 2.00 | 0.88 to 4.56 |
| 0.000 | 0.100 | |||
| ≥5,000 (n = 6) | 6.52 | 1.40 to 30.42 | 9.22 | 0.93 to 91.38 |
| 0.017 | 0.058 | |||
| Radiotherapy | ||||
| No radiation or non-pelvic radiation (n = 357) | 1 | – | 1 | – |
| Pelvic radiation 15–54 Gy (n = 17) | 22.68 | 7.76 to 66.30 | 20.24 | 4.69 to 87.29 |
| <0.001 | <0.001 | |||
The first category of each variable in the first column is the reference category with an odds ratio = 1. Statistically significant results are shown in bold face
Men
Among men, 75.6 % (177/234) were classified as ‘fertile/probably fertile’ and 24.4 % as ‘probably infertile’ (57/234). Twenty-nine percent (34/117) of the male participants who had previously undergone a fertility test reported that possible infertility had been diagnosed. Men who had previously undergone fertility tests received radiotherapy in the pelvic region more often (3.8 %) than those without previous fertility testing (1.4 %, P = 0.074). Out of 59 male study participants who received cumulative cyclophosphamide doses >5,000 mg/m² (but none more than 9,600 mg/m²), eleven reported that their partners became pregnant from them. Of 85 male childhood cancer survivors who had received doses of ifosfamide >42,000 mg/m², eight reported that their partners became pregnant from them.
Six out of the 232 (2.6 %) male participants included in the univariate and multivariable analyses received pelvic irradiation (average dose of 45.7 Gy; ranging from 14 to 60 Gy). Infertile men had significantly received radiation of the pelvic region more often as compared to fertile/probably fertile men. Among the chemotherapeutic drugs, carboplatin and/or cisplatin were associated with an increased likelihood of infertility. Infertile male participants were more likely to have been going through puberty or to have been post-puberty at cancer treatment compared to fertile/probably fertile men (Table 4).
Table 4.
Association of probable infertility in men (n = 57/232) with puberty status at diagnosis and exposure to chemotherapy and/or radiotherapy compared to men who are fertile/probable fertile (n = 177/234)
| Univariate | 95 % CI | Adjusted | 95 % CI | |
|---|---|---|---|---|
| OR | P | OR | P | |
| Puberty status | ||||
| <13 y (n = 164) | 1 | – | 1 | – |
| ≥13 y (n = 68) | 2.13 |
1.14 to 3.99 0.018 |
1.86 |
0.91 to 3.58 0.089 |
| Cyclophosphamide and/or ifosfamide (mg/m2) | ||||
| None (n = 27) | 1 | – | 1 | – |
| 1–4,999/1–41,999 (n = 171) | 1.02 | 0.38 to 2.70 | 1.15 | 0.42 to 3.17 |
| 0.970 | 0.792 | |||
| ≥5,000/≥42,000 (n = 34) | 1.91 | 0.61 to 6.02 | 1.33 | 0.35 to 5.10 |
| 0.270 | 0.674 | |||
| Carboplatin and/or cisplatin (mg/m2) | ||||
| None (n = 202) | 1 | – | 1 | – |
| 1–1,999/1–499 (n = 25) | 1.93 | 0.80 to 4.66 | 2.65 | 0.95 to 7.37 |
| 0.143 | 0.062 | |||
| ≥2,000/≥500 (n = 5) | 2.29 | 0.37 to 14.12 | 2.20 | 0.33 to 14.84 |
| 0.372 | 0.417 | |||
| Etoposide (mg/m2) | ||||
| None (n = 201) | 1 | – | 1 | – |
| 1–4,999 (n = 27) | 0.70 | 0.25 to 1.93 | 0.44 | 0.14 to 1.40 |
| 0.486 | 0.162 | |||
| ≥5,000 (n = 4) | 3.06 | 0.42 to 22.29 | 1.44 | 0.13 to 15.87 |
| 0.270 | 0.768 | |||
| Radiotherapy | ||||
| No radiation or non-pelvic radiation (n = 226) | 1 | – | 1 | – |
| Pelvic radiation 14–60 Gy (n = 6) | 16.73 | 1.91 to 146.43 | 12.22 | 1.18 to 126.70 |
| 0.011 | 0.036 | |||
The first category of each variable in the first column is the reference category with an odds ratio = 1. Statistically significant results are shown in bold face
Discussion
Key results
The present analysis of the first nationwide survey among German adults who survived childhood cancer showed that the strongest risk factor for infertility was irradiation of the pelvic region. Particularly, a high dose of etoposide in female and treatment with carboplatin and/or cisplatin in male and female survivors seemed to increase the likelihood of infertility.
Comparison with other studies
As published previously, the rate of parenthood among participants of this survey was lower than in the general population while the general desire to have children among former patients was comparable to that of the general German population (Hohmann et al. 2011). This discrepancy between a similarly strong wish to have children and at the same time a lower rate of parenthood might indicate fertility impairment. Former study results on laboratory tests (hormone and sperm analyses) with adult long-term survivors of pediatric cancer were similar regarding the proportion of possible infertility found among the subgroup of patients with reported fertility tests in this survey (Rendtorff et al. 2010).
Our finding that irradiation of the pelvic region is gonadotoxic has previously been reported by several studies (Rendtorff et al. 2010, Clemm et al. 2003, Meistrich et al. 2005). For female patients, an increase in the risk of reduced rates of pregnancy has been described for gonadal radiation doses from 5 to 10 Gy (Green et al. 2009). Male patients who receive testicular radiation doses of more than 7.5 Gy have been reported to be less likely of siring a pregnancy (Green et al. 2010).
In female study participants, we found that alkylating agents (cyclophosphamide/ifosfamide) did not increase the likelihood of infertility. This is in contrast to previous results of, e.g., the American Childhood Cancer Survivor Study and a Danish Study (Sonmezer and Oktay 2004; Green et al. 2009; Larsen et al. 2003). However, in our study several participants with high doses of alkylating agents became pregnant. Regarding the question of a prepubertal protective effect with respect to the gonadotoxic effect of alkylating agents, it must be noted that over twice as many female participants evaluated were treated in a prepubertal stage. Studies regarding former female patients who were surveyed at a mean of 12.3 and 14.5 years after treatment for a nephrotic syndrome in childhood or adolescence found no clear association of cyclophosphamide (mean total dosages of 10.3 and 28 g) with fertility impairment (Bogdanovic et al. 1990; Watson et al. 1986). After application of cumulative cyclophosphamide dosages of up to 47.7 g in prepubertal girls, normal menstrual cycles were reported in the follow-up examination (Watson et al. 1986). Possible explanations may include genetic factors affecting drug metabolism increasing the risk of permanent infertility in survivors of childhood cancer (Hudson 2010).
Limitations
Our study results need to be interpreted with caution. Data on treatment characteristics of chemo- and/or radiotherapy were collected prospectively and available from clinical records; however, due to the heterogeneous underlying diagnoses for which pediatric cancer patients were treated with different therapy protocols, the number of patients with high cumulative doses of specific chemotherapeutic agents or radiotherapy did not allow us to determine possible dose–response relationships more accurately.
Regarding the classification of fertility status according to the information provided by a questionnaire, we believe that the self-reported information about pregnancies and children should be valid, at least for female participants. Possible selection bias cannot be ruled out using self-reported results of previous fertility tests. However, we assume that the results of fertility tests should be remembered well by those who underwent these examinations. Obtaining previous test reports for verification or conducting new fertility tests was unfortunately not possible in our nationwide study.
Among the female participants, permanent amenorrhea was used as a criterion for the classification as ‘(probably) infertile’, indicating a possible ovarian failure. Due to hormonal contraceptive use that is resulting in a normal menstrual cycle, this rate can be assumed to be falsely low. One-third of women in the reproductive age-group in Germany take oral contraceptives, and in a subgroup that was taking part in the study ‘hormone and sperm analyses after chemo- and radiotherapy in childhood and adolescence’, 56 % of the participants reported intake of oral contraceptives (Jantke et al. 2011; Wiegratz 2011). Reported menstruation in this study, therefore, was not regarded as a criterion for fertility. Only the statements ‘never had a period’ and ‘period stopped since therapy’ were considered as criteria for infertility.
Participants who reported results from previous fertility testing were more likely to be of post-pubertal status at the time of treatment and older at the time of the survey (Balcerek et al. 2012). They also received radiotherapy in the pelvic region more often compared to those without previous fertility testing, indicating a slight enrichment of this subgroup with participants who were at higher risk of being infertile when deciding for fertility testing.
Conclusions
This is the first nationwide survey evaluating possible infertility in adult survivors of pediatric cancer who are listed in the German Childhood Cancer Registry. Our study showed that infertile adult survivors of childhood cancer had more likely received pelvic radiotherapy as treatment than fertile survivors. Etoposide treatment (in women) and carboplatin and/or cisplatin treatment in both sexes seemed to have an independent risk potential for infertility. Since promising fertility-preserving measures are available, information on treatment-related infertility risk should always be included in the counseling of pediatric cancer patients and their parents. Further research is required, particularly to clarify the gonadotoxicity and possible dose–response relationships of the chemotherapeutic agents used in pediatric oncology.
Acknowledgments
This nationwide survey was supported by the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung). This endowment has the purpose of improving the outcome, treatment and the quality of life of children suffering from cancer by making a significant contribution to optimizing treatment by funding projects aiming to reduce late effects and the evaluation of new approaches to treatment. Furthermore, the study was supported by the Charité University Medical Center in Berlin and the Kind-Philipp Foundation for research in Leukemia (Kind-Philipp-Stiftung für Leukämieforschung) in the Association of Sponsors for the Promotion of German Science (Stifterverband für die Deutsche Wissenschaft) by granting a PhD scholarship. We are grateful to Irene Jung and Dr. Peter Kaatsch of the German Childhood Cancer Registry, Institute of Medical Epidemiology, Biometrics and Informatics (IMBEI), at the University Medical Center of the Johannes-Gutenberg-University Mainz; to all study teams of the German Treatment Optimization Trials; and to all study participants.
Conflict of interest
None.
Abbreviations
- CI
Confidence interval
- GCCR
German Childhood Cancer Registry
- GPOH
German Society for Pediatric Oncology and Hematology
- Gy
Gray
- OR
Odds ratio
- SPSS
Statistical Package for the Social Sciences
Footnotes
Thomas Keil and Anja Borgmann-Staudt have contributed equally to this work.
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