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Pregnancy After Chemotherapy in Male and Female Survivors of Childhood Cancer
TAKE-HOME MESSAGE
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This study evaluated the effects of chemotherapy on pregnancy in male and female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy. This study gathered data from a subset of the Childhood Cancer Survivor Study cohort which followed 5-year survivors of the most common types of childhood cancer treated at 27 institutions in the USA and Canada between 1970 and 1999. The data set included 10 ,938 survivors and 3949 siblings of survivors (the control group) who were studied for a median follow-up of 8 years. The results revealed that 38% of cancer survivors were able to achieve pregnancy compared with 62% of siblings, and 83% of the 38% experienced at least one childbirth compared with 90% of siblings. Comparison of specific chemotherapeutics revealed that greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer.
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The authors conclude that consideration of fertility preservation prior to cancer treatment remains important in maximizing the reproductive potential of all young men and adolescents newly diagnosed with cancer.
– Gautam Jayram, MD
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
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/m(2) increments: HR 0·82, 95% CI 0·79-0·86; p<0·0001). However, in female survivors, only busulfan (<450 mg/m(2) HR 0·22, 95% CI 0·06-0·79; p=0·020; ≥450 mg/m(2) 0·14, 0·03-0·55; p=0·0051) and doses of lomustine equal to or greater than 411 mg/m(2) (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.
Additional Info
Disclosure statements are available on the authors' profiles:
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
Lancet Oncol 2016 May 01;17(5)567-576, EJ Chow, KL Stratton, WM Leisenring, KC Oeffinger, CA Sklar, SS Donaldson, JP Ginsberg, LB Kenney, JM Levine, LL Robison, M Shnorhavorian, M Stovall, GT Armstrong, DM GreenFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The authors have summarized important information from previously published articles on the effects of chemotherapy on future fertility. It has long been recognized that chemotherapy in the form of alkylating agents (eg, cyclophosphamide, ifosfamide, busulfan, etc) are highly toxic agents for reproductive potential. These agents are commonly used for lymphoma (Hodgkin’s/non-Hodgkin’s), ALL, CNS tumors, and bone tumors such as Ewing's sarcoma. Although certain regimens have been associated with nearly 100% azoospermia rates in men (eg, after COPP chemotherapy), the true fertility potential after treatment has not been as clear. This article emphasizes that the fertility effects for men who have been treated for cancer are likely more dramatic than for women, and that the effects are substantial. There is an approximately 43% reduction in fertility for men treated with alkylating agents and 28% reduction for men treated with other drugs.
Since men entering treatment are never certain how many courses or what future treatment may be needed, this article suggests that strong consideration of fertility preservation is necessary. Although we don't have a standard approach for male fertility preservation in the prepubertal individual, consideration of testicular biopsy for tissue cryopreservation is important in the early management of the young male scheduled for treatment. It is also not clear whether some men who did not have children could have been treated more effectively with assisted reproduction (that can be out of reach for some patients based on cost/insurance coverage considerations).
In summary, this article provides important evaluation that quantifies future fertility risk, especially for young men facing chemotherapy treatment for childhood cancers. The results of this study should be clearly understood by all experts in the field, with familiarity on the part of all urologists.