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.