Introduction
Infertility, defined as the inability to achieve a pregnancy after 12 months of unprotected intercourse, is an important late effect of cancer therapy, although the prevalence is challenging to capture accurately. Infertility after childhood cancer therapy typically occurs years after the completion of treatment and often after the patient has transitioned away from pediatric survivor care. As such, most studies evaluating infertility in childhood cancer survivors use surrogate measures such as reduced fertility rates, acute ovarian failure, premature ovarian insufficiency, diminished ovarian reserve, oligo/azoospermia or elevated gonadotropins (1–8). In two studies from the Childhood Cancer Survivor Study, infertility was self-reported by 46% of male survivors compared to 17.5% of healthy siblings (RR 2.64 95% CI 1.88-3.70, p<0.001) and by 13% of female survivors compared to 10% of healthy siblings (RR 1.34 95% CI 1.12-1.60, P= 0.0015).(9,10) National and international working groups have identified cancer therapeutic exposures which place patients at risk for gonadal damage and infertility and have formulated guidelines to assist providers in assessing the extent of injury.(11–13) The exposures identified to result in gonadal dysfunction include: traditional alkylating agent chemotherapy, heavy metal chemotherapy, abdomino-pelvic exposure to radiation, cranial radiation > 30 Gy, surgeries on the reproductive organs and hematopoietic stem cell transplant preparative regimens that include alkylators and/or total body irradiation.(11)
In the survivorship setting, AYA survivors frequently demonstrate little knowledge of infertility risk, are unclear regarding their fertility status and may under- or over-estimate their treatment-related risk for infertility.(14–17) Discussions of infertility risk secondary to cancer treatment should first occur at diagnosis and prior to the initiation of cancer treatment. These discussions should include assessment of fertility preservation candidacy and referrals for appropriate fertility preservation options.(18–20) However, data suggest that these discussions do not uniformly occur as a component of comprehensive oncology care, with great variability occurring among practitioners and across institutions and countries.(21–24) Furthermore, documentation of fertility preservation discussions is generally poor when they do occur.(25,26) Consequently, it is almost impossible to ascertain what information about risk for infertility an individual patient and family actually received at the time of diagnosis. In addition, many AYA survivors do not recall conversations or recall inadequate conversations about infertility risk as part of the initial informed consent for cancer therapy.(14,27,28) Because of these knowledge deficits and misperceptions, most survivors will need to review their level of risk for infertility after completion of treatment at least once and, for many, multiple times in long-term follow-up.
It is also important to realize that survivor care varies significantly between institutions and countries. In the US, it is recommended that survivors are seen regularly and long-term follow-up care be guided by the use of the Children’s Oncology Group (COG) Long-Term Follow-Up Guideline for Survivors of Childhood Adolescent and Young Adult Cancers. The COG guidelines provide recommendations for surveillance to detect sex hormone deficiencies and impaired spermatogenesis and diminished ovarian reserve.(29) International guidelines for surveillance are also available for both males and females. (30,31) The guidelines provide information for consideration of further gonadal testing and referral to specialists. Some centers provide regular comprehensive multidisciplinary follow-up from two years after the completion of therapy throughout life. Other centers do not have providers trained in screening for or identifying specific late, while some centers only follow patients until they transition to adult care. In many cases, adult survivors are followed by generalists with limited knowledge about previous therapies.(32) Additionally, some centers rely upon survivorship clinics to monitor fertility, while others rely upon reproductive endocrinologists and urologists for assessment and counseling of all fertility-related effects. All of these variables result in wide variations in opportunities for survivors to gain meaningful knowledge about their personal risk for infertility or current fertility status.