Advances in Pediatric Oncology

With increasing numbers of children surviving cancer into adulthood, the future complications of exposure to chemotherapy, radiotherapy, and surgery have become evident, including the impairment of gonadal function and fertility. In the general population, females are born with a limited number of follicles that naturally decline with age through atresia, apoptosis, and maturation during menstrual cycles that concludes in menopause at an average age of 52.5 years. Cancer therapies can accelerate this decline, culminating in menopause earlier than would otherwise be expected.

Dr. Jennifer Levine

Jennifer M. Levine, MD, MSW, a pediatric oncologist at NewYork-Presbyterian Komansky Children’s Hospital, has a particular interest in fertility preservation in adolescent and young adults, identifying patients most at risk of impaired fertility. Dr. Levine is an investigator on the National Cancer Institute-funded Childhood Cancer Survivor Study (CCSS), which was established in 1994 to better understand the late effects of cancer treatment, increase survival, and minimize harmful health effects. The CCSS began as a 26-center retrospective cohort study with longitudinal follow-up of 14,364 long-term survivors of childhood cancer in North America diagnosed before the age of 21 years between January 1970 and December 1986. Participants completed comprehensive baseline and follow-up questionnaires that included information regarding demographics and chronic health conditions.

Previous CCSS investigations have demonstrated acute ovarian failure (menopause occurring within 5 years from diagnosis) in 6.3 percent of female survivors and a cumulative incidence of nonsurgical premature menopause (occurs before age 40 but after 5 years from diagnosis that is not related to surgical intervention) in 8 percent of female survivors. Treatments, including higher doses of alkylating agents and increasing doses of radiation therapy to the ovaries, have been associated with premature menopause.

According to the CCSS investigators, little is known regarding the implications of premature menopause on reproductive outcomes in survivors of childhood cancer. To that end, Dr. Levine and her CCSS colleagues sought to provide more accurate estimates of the prevalence of and risk factors for nonsurgical premature menopause in childhood cancer survivors using an additional 7 years of longitudinal follow-up. In this study, for which Dr. Levine served as lead author, the researchers also assessed pregnancy and live birth rates among those survivors who ultimately developed nonsurgical premature menopause. The results of this investigation were published in the January 16, 2018, issue of Cancer.

The CCSS investigators noted that fertility-preserving strategies exist that can improve the chances of cancer survivors having a biologic child despite being exposed to gonadotoxic therapies.

The study compared 2,930 survivors to 1,399 siblings. The patients were diagnosed at a median age of 6 years and were older than 18 years at the time of the current study with a median age of 35 years.

Nonsurgical premature menopause was defined as the cessation of menses ≥6 months in duration that occurred five years after diagnosis and before age 40 and was not due to pregnancy, surgery, or medications. Pregnancy and live birth rates were compared between survivors with and without nonsurgical premature menopause.

The study findings showed:

• 110 childhood cancer survivors developed nonsurgical premature menopause (median age, 32 years), with a prevalence at age 40 years of 9.1 percent
• The odds ratio was 10.5 (95 percent confidence interval) compared with siblings
• Independent risk factors included: exposure to a procarbazine dose ≥4000 mg/m2; any dose of ovarian radiation; ovarian radiation ≥ 500 cGy; and having had a stem cell transplantation
• Compared with survivors without nonsurgical premature menopause, those who developed premature menopause were less likely to ever become pregnant or to have a live birth between ages 31 and 40 years

The CCSS investigators noted that fertility-preserving strategies exist that can improve the chances of cancer survivors having a biologic child despite being exposed to gonadotoxic therapies. Thus, they recommend that healthcare providers educate survivors of childhood cancer regarding their risks of infertility and the fertility preservation options that are available to them.

In the February 2021 issue of Lancet Oncology, the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group – in which Dr. Levine participated – presented recommendations for fertility preservation for female patients diagnosed with childhood, adolescent, and young adult cancer at age 25 or younger. The clinical practice guideline, which is based on available evidence at the time and international expertise, facilitates the care of female patients at high risk for fertility impairment.