With advances in pediatric cancer treatment now allowing more than 80 percent of children to survive at least five years after diagnosis, addressing therapy’s long-term negative consequences is increasingly important. Infertility is a top concern.
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“In the past, the approach had been to try to cure the patient first and deal with the late effects as they came up,” says pediatric hematologist/oncologist Seth Rotz, MD, Director of the High-Five Cancer Survivors Clinic at Cleveland Clinic Children’s. “Because survival has improved, there’s more of an emphasis on reducing long-term impacts, and one of the major ones is infertility. It’s one of the most common and life-altering complications experienced by adults treated for childhood cancers.”
Determinants such as the patient’s gender, age at treatment and genetic makeup influence the risk of permanent infertility. Females treated with chemotherapy without pelvic or cranial radiation fare better than their male counterparts in terms of retaining reproductive potential, recent research shows. Fertility-preserving options prior to pediatric cancer treatment are more plentiful for female patients than for males. If the cancer diagnosis is before puberty, options for both genders are limited and remain experimental.
For those reasons, counseling pediatric patients and their families before treatment about infertility risk and preservation strategies is essential. Research shows that as many as 75 percent of cancer survivors are interested in eventually having children, yet patients frequently aren’t offered fertility preservation options. Lack of knowledge on the part of the medical provider, cost, concerns about delaying cancer treatment, and presumptions about young patients’ lack of interest are all factors.
Such a discussion “can be exceedingly overwhelming for people who’ve just gotten a new cancer diagnosis,” Dr. Rotz says. “The conversation is different, depending on the patient’s age. But it’s kind of amazing how many people want to know what their prospects for having children are, even if it’s a long time away.”
Fertility risk and treatment impact
A precise determination of individual infertility risk is impossible.
“There’s a lot of inter-patient variability, but generally speaking, when we know what chemotherapy regimen a patient is going to receive or what modality is involved, we can give a pretty good prediction of whether they’re closer to 10 percent or 90 percent,” Dr. Rotz says. “For example, if they’re going to get pelvic radiation or a bone marrow transplant, we know those things are particularly high-risk in terms of infertility. It’s the gray area in the middle that is tough for a lot of people.”
Some pediatric cancer treatment regimens have replaced radiation therapy with more intensive chemotherapy, although the effect of modern chemotherapy drugs on patient fertility has not been thoroughly evaluated. A 2016 study analyzed the long-term fertility outcomes of 10,938 five-year survivors of the most common types of childhood cancers who were treated between 1970 and 1999 with contemporary alkylating drugs such as cyclophosphamide but not pelvic or cranial radiotherapy. The data were derived from the Childhood Cancer Survivor Study cohort.
Thirty-eight percent of survivors reported having or siring a pregnancy, compared to a fertility rate of 62 percent among the survivors’ siblings. For male survivors, higher cumulative cyclophosphamide-equivalent doses were strongly associated with a reduced likelihood of siring a pregnancy. For female survivors, most chemotherapy exposures, with the exception of busulfan and high-dose lomustine, did not appear to independently affect the ability to become pregnant, although those women who had not reported a pregnancy by age 30 were unlikely to ever become pregnant, compared with their siblings.
Polymorphisms in genes responsible for cyclophosphamide metabolism may have an impact on germ cell toxicity and subsequent infertility rates. Dr. Rotz and colleagues currently are examining single nucleotide polymorphisms in a large cohort of the Childhood Cancer Survivor Study in an attempt to identify specific genetic variations that affect fertility outcomes after treatment.
The challenge of treatment modification
One means of addressing the future risk of infertility due to pediatric cancer treatment is to modify the therapy to reduce its cytotoxicity. That approach presents challenges, not just because of the potential to impair treatment effectiveness but also to impact other side effects.
“If we have data to go on and know that a patient’s cancer is highly likely to respond to chemotherapy, we can consider giving less chemo,” Dr. Rotz says. “Generally speaking, though, it would be very unlikely for us to decrease the chemotherapy dose to preserve fertility when it would increase the risk of relapse.”
Even when there are multiple comparably effective treatment regimens with varying toxicity profiles, such as with Hodgkin’s lymphoma (HL), the decision involves tradeoffs in terms of side effects, Dr. Rotz says. For example, the BEACOPP regimen (bleomycin, etoposide, Adriamycin, cyclophosphamide, Oncovin, procarbazine and prednisone) provides excellent results in children and adolescents with high-risk HL, without the need for chest radiation — an important consideration for young female patients who would otherwise face a lifetime risk of radiation-induced secondary breast cancer. However, BEACOPP’s procarbazine component imparts a greater than 80 percent likelihood of premature ovarian failure.
Fertility preservation options
Besides treatment modification, the other alternatives when confronting infertility are to attempt to preserve pediatric cancer patients’ reproductive potential prior to therapy, and to use assisted-reproduction techniques when adult survivors desire to start a family.
For prepubescent patients, fertility preservation methods are limited and remain largely investigational. Options for girls are ovarian tissue removal and cryopreservation for later re-implantation (experimental); oocyte extraction for later in vitro fertilization; and, if pelvic radiotherapy is planned, ovarian transposition outside the radiation field. For prepubescent boys, options are testicular tissue extraction and cryopreservation for later sperm extraction (experimental); and gonadal shielding or transposition in the event of radiotherapy.
For postpubescent female patients, options are cryopreservation of embryos, oocytes or ovarian tissue (the latter is experimental); ovarian function suppression using gonadotrophin-releasing hormone agonists (to be considered only when proven cryopreservation methods aren’t feasible, since GnRHA efficacy is equivocal); ovarian transposition; and conservative (fertility-sparing) gynecologic surgery, if possible, in the event of ovarian or cervical cancer. For postpubescent males, options are sperm or testicular tissue cryopreservation; and gonadal shielding or transposition.
Some female patients may be reluctant to consider embryo/oocyte cryopreservation as an option because of the need to retrieve eggs at the beginning of the ovulatory cycle, which could delay cancer treatment by as much as six weeks, depending on the patient’s menstrual phase at diagnosis. To address this concern, Dr. Rotz notes that Cleveland Clinic is among the institutions offering the random-start ovarian stimulation protocol, which uses hormone stimulation to reduce the cycling period without compromising oocyte yield or quality, allowing cancer treatment to begin in two to three weeks.
The advantage of being treated at a large academic medical center such as Cleveland Clinic is the access to advanced cancer and fertility preservation services available in the same institution, delivered by medical providers who routinely collaborate on multi-disciplinary teams.
“My job in the survivorship clinic is to screen patients, have a general conversation with them and their family members about fertility preservation, and refer them to our experts if the patient wishes. It’s a huge benefit to have all of those services readily available, right here in one system.”