Low Risk for Infertility in Female Childhood Cancer Survivors

Roxanne Nelson, BSN, RN

March 23, 2016

The long-term impact of modern chemotherapy regimens on the future fertility of female childhood cancer survivors appears to be small, but the news is less optimistic for men.

The findings comes from a study that traced 10,938 childhood cancer survivors, and compared them with 3949 siblings.

By age 45, 70% of female cancer survivors had been able to conceive, compared with more than 80% of the siblings.

However, for men, only 50% had fathered a child, compared with 80% of the siblings.

The study was published online March 22 in the Lancet Oncology.

"The main implication of this study is that it shows that boys and men remain at substantial risk of reduced fertility, although girls and women appear to be more protected," said lead author Eric Chow, MD, professor of pediatrics at the University of Washington in Seattle.

"Our study also provides a more detailed assessment of risk associated with individual drugs and their doses, so clinicians could use that information to provide more accurate counseling regarding risks for individual patients and better identify who might benefit from upfront fertility preservation," Dr Chow told Medscape Medical News.

In their study, the authors looked at the impact of 14 commonly used chemotherapy agents, given at various doses, on pregnancy and live birth.

High cumulative doses of several alkylating drugs, including cyclophosphamide, ifosfamide, procarbazine, and cisplatin, were linked to a significantly reduced likelihood of pregnancy for male survivors.

Among women, only busulfan and high doses of lomustine appeared to be directly linked to decreased fertility.

Older maternal age was also associated with a reduced likelihood of pregnancy and childbirth, possibly because of premature menopause from chemotherapy exposure.

The authors note that these results should "provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain."

Options for Young Patients

Dr Chow explained that physicians need to do a "better job discussing fertility and fertility preservation options with patients and families upfront before starting cancer treatment. "

Specifically, boys who are diagnosed with cancer after puberty should be encouraged to bank their sperm to maximize their reproductive options in the future.

"I'm not sure if there are numbers of how many boys/men have this discussion currently, but historically — in studies done in the last 10 to 20 years — as many as 50%, or more, of male survivors have reported not having this discussion with their healthcare team," Dr Chow said. "I suspect it could be better now, but doubtful that is anywhere close to 0%," he said.

Current options for women are more complicated, Dr Chow explained.

"Oocyte cryopreservation is challenging because of the cost and the time required, especially in aggressive cancers where there may not be the luxury of a 2- or 3-week delay in starting treatment," he said.

That said, girls and women do remain at some risk for infertility, particularly if there might be exposure to high doses of alkylating chemotherapy and if there was radiation to the pelvis, regardless of chemotherapy, Dr Chow pointed out.

"Our results suggest that fertility could still remain compromised, particularly among women who delay pregnancy until 30+ years," he said. "Thus, it seems very reasonable for female survivors of childhood/adolescent cancer to at least have a conversation with a reproductive fertility specialist when they are adult-aged and thinking of having children at an older age."

Fertility Issues a "Long Way Off"

This study will allow for more accurate counseling of patients concerning their individual risks, Richard Anderson, MD, Elsie Inglis Professor of Clinical Reproductive Science at the University of Edinburgh, United Kingdom, and Hamish Wallace, MD, from the Royal Hospital for Sick Children in Edinburgh, write in an accompanying comment.

"This is certainly a step toward better information for patients," Dr Anderson told Medscape Medical News. "The key issue, however, is that the patients involved are children and adolescents, so fertility is a long way off for them, and may be a difficult concept to grasp."

Semen cryopreservation is fairly straightforward, but substantial gaps remain in its provision and accessibility. "Sperm banking is widely available in theory, but in practice it may be more difficult, especially for embarrassed teenagers," he explained.

Another challenge are prepubertal and peripubertal boys, for whom semen cryopreservation is not possible.

"There are developments for new technologies for prepubertal testis storage, but they remain experimental," Dr Anderson said. "A number of centers across Europe are offering this, although they don't know what to do with the stored testis tissue yet. There are no clear ways to protect testes, although there are various lab studies underway."

For girls and young women, where the picture is generally more positive, these data emphasize the need to accurately identify the relatively small proportion of those who are at high risk for infertility, Drs Anderson and Wallace explain. This will eliminate the need to subject women at low risk to what might be invasive procedures.

"I think accurate identification is an important way forward, but these are girls/adolescents, not women," said Dr Anderson. "Ovarian tissue storage is one possibility, oocyte storage is another for the older ones."

"Girls with newly diagnosed cancer face a battery of invasive/demanding tests for staging and other things, so having a laparoscopy for ovarian tissue storage needs to be clearly justified," he added.

Details of the Results

There has been a growing emphasis on reducing the burden of long-term effects, including those on fertility, in childhood cancer survivors.

Previous research has identified several chemotherapeutic agents, primarily alkylating drugs, as being associated with lowering fertility, the authors note.

However, there is limited information about the dose effects on reproductive outcomes from newer drugs, such as ifosfamide, in survivors of childhood cancer.

The goal of the current study was to establish the effects of contemporary chemotherapy drugs on pregnancy in both male and female survivors of childhood cancer who were not exposed to pelvic or cranial radiotherapy.

Dr Chow and his colleagues used data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors (n = 10,938) of the most common types of childhood cancer who were diagnosed before age 21 and treated at 27 institutions in the United States and Canada from 1970 to 1999.

They examined the cumulative doses of 14 drugs (busulfan, carboplatin, carmustine, chlorambucil, chlormethine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, procarbazine, temozolomide, and thiotepa) and evaluated the independent effects of each drug on subsequent pregnancies and live births.

Doses of these drugs (except carboplatin, cisplatin, dacarbazine, and temozolomide) were converted into a cyclophosphamide-equivalent dose.

The siblings of survivors (n = 3949) made up the comparison group.

At a median follow-up of 8 years (from cohort entry or at age 15), 4149 (38%) survivors reported a pregnancy and 3453 (83%) individuals reported at least one live birth.

Conversely, after a median follow up of 10 years, 2445 (62%) siblings reported a pregnancy, 2201 (90%) of whom reported at least one live birth.

Multivariable analysis showed that male survivors had a lower likelihood of pregnancy than their siblings (hazard ratio [HR], 0.63; P < .0001), as did female survivors (HR, 0.87; P < .0001). Male survivors also had a lower likelihood of having a live birth than their siblings (HR, 0.63; P < .0001), as did female survivors (HR, 0.82; P < .0001).

Among the male survivors, the reduced likelihood of siring a pregnancy was associated with higher doses of cyclophosphamide (HR, 0.60; P < .0001), ifosfamide (HR, 0.42; P = .0069), procarbazine (HR, 0.30; P < .0001), and cisplatin (HR, 0.56; P = .0023).

Among the female survivors, a lower incidence of pregnancy was associated with busulfan at doses below 450 mg/m² (HR, 0.22; P = .02), busulfan at doses of 450 mg/m² or higher (HR, 0.14; P = .0051), and lomustine at doses of 411 mg/m² or higher (HR, 0.41; P = .046).

In men, a cyclophosphamide-equivalent dose was significantly associated with a decreased likelihood of siring a pregnancy per 5000 mg/m² increments (HR, 0.82; P < .0001), but in women, the risk was only noted at the highest doses when analyzed by quartile (HR for upper quartile vs no exposure, 0.85; P = .023).

The study was funded by the National Cancer Institute, the National Institutes of Health, and the American Lebanese–Syrian Associated Charities. Dr Chow, Dr Anderson, and Dr Wallace have disclosed no relevant financial relationships.

Lancet Oncol. Published online March 22, 2016. Abstract, Comment


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