Predicting acute ovarian failure in female survivors of childhood cancer: a cohort study in the Childhood Cancer Survivor Study (CCSS) and the St Jude Lifetime Cohort (SJLIFE).
Summary (2 min read)
Introduction
- Due to advancements in cancer treatment and supportive care, there are almost 500,000 survivors of childhood cancer in the United States, 1 and between 300,000 and 500,000 childhood cancer survivors in Europe.
- AOF occurs when an individual permanently stops menstruating within five years of their cancer diagnosis, or fails to progress through puberty or to achieve menarche by 18 years of age following cancer treatment.
- Obtaining an accurate risk estimate is important as available fertility preservation technologies such as ovarian tissue and oocyte cryopreservation are expensive and invasive.
- The operative risk may be elevated in children who are immunocompromised or have abnormal blood counts, increasing their risk for infection or bleeding.
Study design and participants
- The CCSS, a multi-institutional longitudinal cohort study of 24,362 survivors of childhood cancer from North America, was the primary source of data.
- Originally established in 1994, its cohort characteristics, eligibility criteria, and study design features have been documented elsewhere.
- Survivors were eligible for the AOF prediction analysis if they were female, had complete treatment exposure data, were at least 18 years of age at their latest follow-up, and provided menstrual history information including age at menarche, current menstrual status, age at last menstrual period, and etiology of menopause (surgical vs. nonsurgical) for those who were currently menopausal.
- 4, 20 Participants were eligible for SJLIFE if they had been diagnosed and treated for a paediatric cancer at St. Jude Children's Research Hospital after 1962 and were at least ten-year survivors.
- Ethics approval for the study was obtained from the University of Alberta Health Research Ethics Board (PRO00067066).
Procedures
- Self-reported demographic and outcome information was obtained from CCSS participants through baseline and follow-up questionnaires, and treatment exposure information was abstracted from medical and radiation records.
- 8 Classification of ovarian status, the primary outcome, was assigned to CCSS participants using an established definition, 6 or manually by endocrinologists (SM-M, CAS) for ambiguous cases, based on responses to menstrual history questions on baseline and/or follow-up questionnaires.
- Individuals who had not experienced menarche were classified with AOF if menarche was not achieved by age 18.
- As ovarian radiation dose information is not universally available, the authors also considered a prescribed dose model where the ovarian radiation dose term was replaced with protocol-specified abdominal and pelvic radiation doses while retaining all other variables.
- Model performance was evaluated using the average predicted risk and the observed AOF status.
Statistical analysis
- The ovarian status was deemed not assessable for participants who were exposed to a pituitary radiation dose > 30 Gray (Gy), who had a tumour in the hypothalamus/pituitary region, or whose menstrual history information was incomplete, unclear, or provided by a proxy.
- Thus, these survivors were excluded from the analysis.
- The authors developed candidate prediction algorithms using three popular methods for binary outcome analysis (logistic regression, random forest, and support vector machines), which allows for examination of the sensitivity of the data to the modelling method.
- The best ovarian dose and prescribed dose models were selected from these candidate prediction algorithms and subsequently externally validated [27] [28] [29].
- The AP value can be interpreted as the AOF risk for a patient whose predicted risk is greater than the risk estimate of a randomly selected female survivor with AOF.
Of
- Table 2 and Table 3 present the results of categorising CCSS and SJLIFE patients into the predefined risk categories for the ovarian dose model and prescribed dose model, respectively.
- The ovarian dose model categorised survivors more precisely and accurately than the prescribed dose model, as seen by the larger counts in the high (≥ 50%) and low (< 5%) risk groups.
- On the other end of the predicted risk spectrum, the ovarian dose model classified 182 individuals as high risk (of whom 132 were AOF cases, 725%), while the prescribed dose model predicted only 97 individuals as high risk with 61 (629%) having developed AOF.
- A cross-table of the risk estimates from the prescribed dose and ovarian dose models based on CCSS cohort and a detailed comparison is included in the Supplementary Material (pages 2, 5).
Discussion
- With AUC values from 078 to 082 in the CCSS cohort and 094 to 096 in the external validation using the SJLIFE cohort, the authors have developed, to their knowledge, the first risk prediction models for AOF that provide a high level of confidence appropriate for use in a clinical setting.
- 8, 22, 23 Although the authors developed the models using the outcome data with a higher potential for misclassification, they observed an increase in the predictive ability in the SJLIFE cohort, which highlights the robustness of their models.
- A continuous AOF risk estimate and corresponding risk category is calculated from the ovarian dose and/or prescribed dose model depending on the radiation information provided.
- Further, it is important that cancer survivors deemed to be at high risk for AOF do not assume that they will develop ovarian failure and use appropriate contraception to prevent unplanned pregnancies and sexually transmitted infections.
- Eighty-four survivors in the CCSS cohort who were classified as non-AOF started OCP use within 5 years of their cancer diagnosis and were thus at risk for misclassification, but detailed review by the two study endocrinologists minimized this risk.
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Frequently Asked Questions (10)
Q2. What have the authors stated for future works in "Predicting acute ovarian failure in female childhood cancer survivors: a cohort study in the childhood cancer survivor study (ccss) and the st. jude lifetime cohort (sjlife) authorship list line" ?
Their goal was to develop and validate an easily accessible and user-friendly clinical tool to aid clinicians at the time of cancer diagnosis by providing personalised risk assessments of future ovarian function for patients. The outstanding performance in the external SJLIFE cohort further confirms that their prediction algorithms are generalisable. CCSS participant ovarian status was not verified clinically, and thus subject to potential misclassification. 8,22,23 Although the authors developed the models using the outcome data with a higher potential for misclassification, they observed an increase in the predictive ability in the SJLIFE cohort, which highlights the robustness of their models.
Q3. What is the main focus of cancer survivorship research?
As the majority of childhood cancer patients will become long-term survivors, the focus of cancer survivorship research has shifted toward maximizing survivor quality of life.
Q4. How many CCSS survivors had a HSCT?
Almost one-third (1,869 (31·8%) of 5,886) of the CCSS survivors had been diagnosed with leukaemia, and 3·7% (217 of 5,886) underwent a HSCT.
Q5. What predictors were used in the CCSS and SJLIFE models?
Common predictors in both models were history of hematopoietic stem cell transplantation (HSCT), cumulative alkylating agent dose, and an interaction between age at cancer diagnosis and HSCT.
Q6. How many survivors were diagnosed with AOF in the CCSS sample?
Three hundred and fifty-three of 5,886 survivors were classified with AOF in the CCSS sample, corresponding to a prevalence of 6·0%.
Q7. What was the ovarian dose model AUC value?
The ovarian dose model AUC value was 0·94 (95% CI = 0·90-0·98), and the prescribed dose model AUC value was 0·96 (95% CI = 0·94-0·97).
Q8. How much is the prevalence of premature menopause in CCSS female survivors?
In the general population, the prevalence of premature, non-surgical menopause is approximately 1%,11 whereas the cumulative incidence of PM (excluding AOF) reported in CCSS female survivors is 9% by age 4010.
Q9. What was the AP value for the ovarian dose model?
For internal validation using the CCSS test sets, the AP value was 0·50 (95% CI = 0·45-0·56) for the ovarian dose model and 0·37 (95% CI = 0·32-0·43) for the prescribed dose model.
Q10. What is the affiliation between MD Anderson and the St Jude Hospital Research Center?
MD Anderson Late Effects Group (RMH and SAS) has a subcontract with St Jude Hospital Research Center for CCSS dosimetry and also a contract from REB/NCI to perform dosimetry on various studies.