1. Carlson, Robert H.

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Female survivors of childhood cancer who wish to have children can take heart from a new analysis of the Childhood Cancer Survivor Study (CCSS).

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In a study of survivors of childhood cancer treated with chemotherapy but not radiotherapy to the pelvis or brain between 1970 and 1999, the likelihood of a female survivor becoming pregnant and giving birth was statistically similar to that of their female siblings. The study was published in The Lancet Oncology (2016;17:567-76).


The picture was not as rosy for males.


In multivariate analysis, male survivors had a decreased likelihood of siring a pregnancy compared with siblings, with a hazard ratio of 0.63, compared with female survivors who had a hazard ratio of 0.87 of having a pregnancy.


The hazard ratios of having a live birth were 0.63 for male survivors and 0.82 for female survivors.


In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide, ifosfamide, procarbazine, and cisplatin.


In female survivors, only busulfan and doses of lomustine equal to or greater than 411 mg/m2 were significantly associated with reduced pregnancy and live birth. Cyclophosphamide was associated with risk only at the highest doses for females.


"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," said lead author Eric J. Chow, MD, Assistant Professor in the Department of Pediatrics at the University of Washington, Seattle, and Assistant Member, Fred Hutchinson Cancer Research Center.


"Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximize the reproductive potential of all adolescents newly diagnosed with cancer," Chow added.


The study included data on 10,938 patients in the CCSS, which followed five-year survivors of the most common types of childhood cancer diagnosed before age 21 years.


The comparison group comprised 3,949 siblings of survivors.


The researchers focused on doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records. They 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 live births occurring between ages 15 years and 44 years.


Overall, at a median follow-up of eight years from cohort entry or at age 15 years, whichever was later, only 38 percent (4,149) of survivors reported having or siring a pregnancy compared with 62 percent (2,445) of siblings.


Relevance Today

The data, even though based on cases treated several decades ago, are still relevant today, Chow said in an interview with OT.


"The basis of chemotherapy for pediatric oncology patients, which are most of the drugs cited in the study, are cytotoxics still in use today," Chow said.


Chow said the reasons for lower childbearing among cancer survivors compared with siblings is more than ovarian failure.


"Even among women who did not get alkylating agents there is difference in outcomes," he said. "There are social factors that we know from other studies are more pronounced in childhood cancer survivors that may decrease the likelihood of having children, such as being less likely to be married or in a stable long-term relationship.


"And people who have had cancer may be reluctant to have children because it has been reported that some are afraid they may pass the risk to any offspring."


The greater difference between survivors and their siblings for men suggests that males are more sensitive to the effects of these chemotherapy drugs, Chow said.


"The good news for male pediatric patients is that fertility preservation in the form of sperm banking is easier than egg preservation," he said. "But studies show that at least half of eligible adolescent males are not having their sperm banked even when they are likely to be exposed to treatment that may affect fertility."


Men and women who have had cancer as children or adolescents should be aware of their risks and should consider talking with a reproductive specialist if they want to have children later in life, Chow advised.


The study was funded by the National Cancer Institute and the American Lebanese Syrian Associated Charities, the fundraising foundation of St. Jude Children's Research Hospital.



Fertility is a key concern for young patients with newly diagnosed cancer and this study provides a basis for more accurate counseling of patients as to their individual risks, said Richard A. Anderson, MD, PhD, Professor of Clinical Reproductive Science and Head of Section, Obstetrics and Gynecology, University of Edinburgh, U.K., in a commentary that accompanied the study (Lancet Oncol 2016;17:540-41).


"Recognition of the adverse effects of radiotherapy has led to the development of protocols reducing or eliminating radiotherapy, and there is growing reliance on regimens of chemotherapy alone," Anderson said. Therefore, "a detailed analysis such as this study is needed on the effect of chemotherapy regimens when used without radiotherapy to assess the effects of contemporary treatment protocols on subsequent fertility."


A key strength of Chow's study, Anderson said, is the detailed documentation of the chemotherapeutic regimens, particularly alkylating and DNA crosslinking drugs.


He noted the report shows some evidence of increasing risk with age, although the numbers were small.


"This finding might indicate acceleration of the effect of reproductive aging, such that the effects on female fertility only become apparent when natural fertility is in decline in the later reproductive years," Anderson said.


The report focuses attention on how best to develop strategies for the protection of fertility in young patients with cancer, he said.


Also, awareness is needed of the risk of loss of fertility in male patients treated with alkylating drugs and cisplatin, and for pretreatment referral to fertility services.


What is lacking is an analysis of conception difficulties in childhood cancer survivors-that is, the experience of infertility-recognizing ovarian failure is not the only cause of inability to conceive, Anderson said.


Robert H. Carlson is a contributing writer.