Recommendations for Premature Ovarian Insufficiency Surveillance for Female Survivors of Childhood, Adolescent, and Young Adult Cancer: A Report From the International Late Effects of Childhood Cancer Guideline Harmonization Group in Collaboration With the PanCareSurFup Consortium

Abstract

Purpose: Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with alkylating agents and/or radiation, with potential exposure of the ovaries, have an increased risk of premature ovarian insufficiency (POI). Clinical practice guidelines can facilitate these survivors' access to optimal treatment of late effects that may improve health and quality of survival; however, surveillance recommendations vary among the existing long-term follow-up guidelines, which impedes the implementation of screening.

Patients and methods: The present guideline was developed by using an evidence-based approach and summarizes harmonized POI surveillance recommendations for female survivors of CAYA cancer who were diagnosed at age < 25 years. The recommendations were formulated by an international multidisciplinary panel and graded according to the strength of the evidence and the potential benefit gained from early detection and intervention. The harmonized POI surveillance recommendations were developed by using a transparent process and are intended to facilitate care for survivors of CAYA cancer.

Results and conclusion: The harmonized set of POI surveillance recommendations is intended to be scientifically rigorous, to positively influence health outcomes, and to facilitate the care for female survivors of CAYA cancer.

Fig 1.

Harmonized recommendations for POI surveillance in survivors of CAYA cancer. Premature ovarian insufficiency (POI) is defined as a clinical condition developing in any adult female before age 40 years that is characterized by the absence of menses for ≥ 4 months and two elevated serum follicle-stimulating hormone (FSH) levels in the menopausal range (on the basis of the maximum threshold of the laboratory assay used). *Treatments with evidence of causing POI include alkylating agents in general (level A evidence), cyclophosphamide, procarbazine (level C evidence), and radiotherapy to a field that includes the ovaries (level A evidence). †At least annually, with increasing frequency as clinically indicated based on growth and pubertal progression. ‡At least for girls of 11 years of age and older, and for girls with primary amenorrhoea (age 16). §If amenorrhoea, measure FSH and oestradiol randomly; if oligomenorrhoea, measure during early follicular phase (day 2-5). ∥This assessment should be performed after ending oral contraceptive pill/sex steroid replacement therapy use, ideally after two months without oral contraceptive pills. ¶The absence of initiation of puberty (Tanner stage 2 breast development) in girls 13 years or older or failure to progress in pubertal stage for ≥ 12 months. AMH, anti-Müllerian hormone; CAYA, childhood, adolescent, and young adult; Level A, high level of evidence; Level B, moderate/low level of evidence; Level C, very low level of evidence.

Fig 2.

The effective (shown in blue) sterilizing doses of radiation are illustrated for a known age at treatment. Above the gold/blue boundary, doses to the ovary will cause immediate POI for most patients due to depletion of the non-growing follicle population to below 1,000. Reprinted with permission from Anderson et al.

Fig 3.

The cumulative incidence of nonsurgical menopause in female survivors of childhood cancer demonstrating increasing incidence of menopause with advancing age and relationship to gonadotoxic cancer therapy. (A) Treatment with alkylating agents (AA); (B) treatment with abdominal-pelvic radiotherapy (A-P RT) only; and (C) treatment with AA plus A-P RT, which was associated with the highest incidence. NOTE. Study cohort does not include females who developed ovarian failure within the first 5 years. Reprinted with permission from Sklar et al.