Elsevier

The Lancet Oncology

Volume 17, Issue 5, May 2016, Pages 567-576
The Lancet Oncology

Articles
Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort

https://doi.org/10.1016/S1470-2045(16)00086-3Get rights and content

Summary

Background

The effect of many contemporary chemotherapeutic drugs on pregnancy and livebirth is not well established. We aimed to establish the effects of these drugs on pregnancy in male and female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy.

Methods

We used data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors of the most common types of childhood cancer who were diagnosed before age 21 years and treated at 27 institutions in the USA and Canada between 1970 and 1999. We extracted doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records. We used sex-specific Cox models to establish the independent effects of each drug and the cumulative cyclophosphamide equivalent dose of all drugs in relation to pregnancies and livebirths occurring between ages 15 years and 44 years. We included siblings of survivors as a comparison group.

Findings

We included 10 938 survivors and 3949 siblings. After a median follow-up of 8 years (IQR 4–12) from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years (IQR 6–15), 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. In multivariable analysis, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio [HR] 0·63, 95% CI 0·58–0·68; p<0·0001; female survivors: 0·87, 0·81–0·94; p<0·0001) or of having a livebirth (male survivors: 0·63, 0·58–0·69; p<0·0001; female survivors: 0·82, 0·76–0·89; p<0·0001). In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide (HR 0·60, 95% CI 0·51–0·71; p<0·0001), ifosfamide (0·42, 0·23–0·79; p=0·0069), procarbazine (0·30, 0·20–0·46; p<0·0001) and cisplatin (0·56, 0·39–0·82; p=0·0023). Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy (per 5000 mg/m2 increments: HR 0·82, 95% CI 0·79–0·86; p<0·0001). However, in female survivors, only busulfan (<450 mg/m2 HR 0·22, 95% CI 0·06–0·79; p=0·020; ≥450 mg/m2 0·14, 0·03–0·55; p=0·0051) and doses of lomustine equal to or greater than 411 mg/m2 (0·41, 0·17–0·98; p=0·046) were significantly associated with reduced pregnancy; cyclophosphamide equivalent dose was associated with risk only at the highest doses in analyses categorised by quartile (upper quartile vs no exposure: HR 0·85, 95% CI 0·74–0·98; p=0·023). Results for livebirth were similar to those for pregnancy.

Interpretation

Greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer. However, our findings should provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy-specific effects on pregnancy were generally few. Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximise the reproductive potential of all adolescents newly diagnosed with cancer.

Funding

National Cancer Institute, National Institutes of Health, and the American Lebanese–Syrian Associated Charities.

Introduction

Nowadays, more than 80% of children with cancer become long-term survivors, and reproductive health is a leading concern in young adult survivors.1, 2 As such, there is a growing emphasis on reducing the burden of long-term effects—including adverse effects on fertility—partly by reducing exposure to radiation and increasing reliance on chemotherapy.3, 4 Previous studies5, 6 have identified some chemotherapeutic drugs, mainly alkylating drugs, as being associated with reduced fertility in both sexes. However, little is known about the dose effects on reproductive outcomes from newer drugs, such as ifosfamide and similar DNA interstrand crosslinking drugs (ie, cisplatin and carboplatin), in survivors of childhood cancer. For example, guidelines from the Children's Oncology Group (COG) rate the evidence for effects of DNA interstrand crosslinking drugs on gonadal function as “uniform but lower-level supporting evidence” for both sexes, and more detailed dose-threshold information for conventional alkylating drugs is absent for female survivors.7

Research in context

Evidence before this study

We searched PubMed from 1966 up until June 1, 2015, for English-language publications, with the keywords “childhood cancer”, “survivor”, “fertility”, “pregnancy”, “birth”, “ovary”, and “sperm”. We additionally examined the bibliographies of selected references. Most of the previous literature, including analyses from the Childhood Cancer Survivor Study, included large numbers of individuals exposed to radiotherapy with known effects on gonadal function (ie, radiation to the gonads or the hypothalamic–pituitary axis). We identified only a few analyses (most with sample sizes <50) that specifically examined the effects of newer chemotherapeutic drugs, such as ifosfamide and cisplatin, in survivors of childhood cancer who were not exposed to such radiotherapy.

Added value of this study

This is one of the largest studies of pregnancy and livebirth in cancer survivors of any age who were not exposed to gonadal or cranial radiation. Importantly, our study features a broad range of commonly used chemotherapy drugs, given at varying doses, which allowed us to establish more precise dose thresholds associated with reduced likelihood of siring a pregnancy or livebirth for male and female survivors of childhood cancer. Our findings show an association between risk and exposure to cisplatin, a finding not consistently reported in survivors of childhood cancer. Female survivors can be reassured by the result that chemotherapy-specific effects in women who did not receive any radiotherapy to the pelvis or brain were generally few in relation to these reproductive outcomes, except with exposure to the highest cumulative doses.

Implications of all the available evidence

Counselling of patients and families about fertility preservation before initiation of cancer therapy is important. In particular, sperm banking should be encouraged for all newly diagnosed pubertal men, since this is a proven method of fertility preservation. The association of risk with cisplatin exposure should be investigated further, given the increase in use of that drug in many contemporary paediatric treatment protocols.

Beginning in 2008, the Childhood Cancer Survivor Study (CCSS) expanded to include more than 10 000 5-year survivors treated from 1987 to 1999. This expansion provided an opportunity to examine the reproductive effects of these newer drugs in detail. Combined with the original CCSS cohort treated from 1970 to 1986, we examined the effects of alkylator and DNA interstrand crosslinking drugs on pregnancy and livebirth in a subset of the cohort not exposed to pelvic or cranial radiotherapy.

Section snippets

Study design and participants

Study methods and participant accrual in the CCSS have been reported previously.8 We included individuals in the CCSS who were diagnosed before age 21 years with the most common types of childhood cancer (all leukaemia types, CNS tumour, lymphoma, kidney tumour, neuroblastoma, soft-tissue sarcoma, and bone tumour) and treated at 27 institutions in the USA and Canada between 1970 and 1999, and who survived at least 5 years after diagnosis. To be consistent with national birth data and previous

Results

Figure 1 shows the cohort profile. We included 10 938 survivors and 3949 siblings. 8631 (79%) survivors were treated with chemotherapy, with 5922 (54%) receiving at least one alkylating or similar DNA interstrand crosslinking drug (table 1, appendix). Among survivors who were treated with one of the 14 drugs of interest, the median number of drugs received was one (IQR one to two), with 2335 (21%) survivors receiving two or more drugs. The maximum number of drugs received was six. The

Discussion

On the basis of the gradual elimination of radiotherapy from many paediatric treatment regimens over time, replaced, in many instances, by more intensive chemotherapy,3, 4 we sought to identify the effect of chemotherapy alone on pregnancy and livebirth. Few well powered analyses have examined the dose–response association of individual chemotherapeutic drugs without radiotherapy across a broad range of cancer diagnoses and chemotherapeutic drugs in this population, particularly in regard to

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