Elsevier

The Lancet Oncology

Volume 21, Issue 3, March 2020, Pages 436-445
The Lancet Oncology

Articles
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)

https://doi.org/10.1016/S1470-2045(19)30818-6Get rights and content

Summary

Background

Cancer treatment can cause gonadal impairment. Acute ovarian failure is defined as the permanent loss of ovarian function within 5 years of cancer diagnosis. We aimed to develop and validate risk prediction tools to provide accurate clinical guidance for paediatric patients with cancer.

Methods

In this cohort study, prediction models of acute ovarian failure risk were developed using eligible female US and Canadian participants in the Childhood Cancer Survivor Study (CCSS) cohort and validated in the St Jude Lifetime Cohort (SJLIFE) Study. 5-year survivors from the CCSS cohort were included if they were at least 18 years old at their most recent follow-up and had complete treatment exposure and adequate menstrual history (including age at menarche, current menstrual status, age at last menstruation, and menopausal aetiology) information available. Participants in the SJLIFE cohort were at least 10-year survivors. Participants were excluded from the prediction analysis if they had an ovarian hormone deficiency, had missing exposure information, or had indeterminate ovarian status. The outcome of acute ovarian failure was defined as permanent loss of ovarian function within 5 years of cancer diagnosis or no menarche after cancer treatment by the age of 18 years. Logistic regression, random forest, and support vector machines were used as candidate methods to develop the risk prediction models in the CCSS cohort. Prediction performance was evaluated internally (in the CCSS cohort) and externally (in the SJLIFE cohort) using the areas under the receiver operating characteristic curve (AUC) and the precision-recall curve (average precision [AP; average positive predictive value]).

Findings

Data from the CCSS cohort were collected for participants followed up between Nov 3, 1992, and Nov 25, 2016, and from the SJLIFE cohort for participants followed up between Oct 17, 2007, and April 16, 2012. Of 11 336 female CCSS participants, 5886 (51·9%) met all inclusion criteria for analysis. 1644 participants were identified from the SJLIFE cohort, of whom 875 (53·2%) were eligible for analysis. 353 (6·0%) of analysed CCSS participants and 50 (5·7%) of analysed SJLIFE participants had acute ovarian failure. The overall median follow-up for the CCSS cohort was 23·9 years (IQR 20·4–27·9), and for SJLIFE it was 23·9 years (19·0–30·0). The three candidate methods (logistic regression, random forest, and support vector machines) yielded similar results, and a prescribed dose model with abdominal and pelvic radiation doses and an ovarian dose model with ovarian radiation dosimetry using logistic regression were selected. Common predictors in both models were history of haematopoietic stem-cell transplantation, cumulative alkylating drug dose, and an interaction between age at cancer diagnosis and haematopoietic stem-cell transplant. External validation of the model in the SJLIFE cohort produced an estimated AUC of 0·94 (95% CI 0·90–0·98) and AP of 0·68 (95% CI 0·53–0·81) for the ovarian dose model, and AUC of 0·96 (0·94–0·97) and AP of 0·46 (0·34–0·61) for the prescribed dose model. Based on these models, an online risk calculator has been developed for clinical use.

Interpretation

Both acute ovarian failure risk prediction models performed well. The ovarian dose model is preferred if ovarian radiation dosimetry is available. The models, along with the online risk calculator, could help clinical discussions regarding the need for fertility preservation interventions in girls and young women newly diagnosed with cancer.

Funding

Canadian Institutes of Health Research, Women and Children's Health Research Institute, National Cancer Institute, and American Lebanese Syrian Associated Charities.

Introduction

Because of advancements in cancer treatment and supportive care, there are almost 500 000 survivors of childhood cancer in the USA,1 and between 300 000 and 500 000 survivors of childhood cancer in Europe.2, 3 Survivors are at an increased risk of developing chronic health conditions from toxicities related to cancer treatment.4 The cumulative burden of treatment-assciated chronic health conditions is substantial, with survivors experiencing an average of 17 conditions by the age of 50 years (eg, endocrinal dysfunction, cardiac disease, and neurocognitive difficulties).5 Impaired gonadal function is a common late effect of cancer therapy that can have a substantial impact on a survivor's quality of life.6

Research in context

Evidence before this study

An increased risk of premature gonadal failure has been shown in survivors of paediatric cancer treated with chemotherapy and radiotherapy. 6% of female survivors of childhood cancer lose ovarian function within 5 years of treatment (acute ovarian failure), and an additional 9% have premature, non-surgical menopause before the age of 40 years. The timeframe between primary cancer diagnosis and treatment resulting in acute ovarian failure is short to identify high-risk patients that will benefit from interventions aimed at fertility preservation. We searched PubMed with no date or language restrictions for all studies to evaluate the current knowledge of acute ovarian failure and the associated risk factors in survivors of childhood cancer using the search terms “pediatric cancer OR childhood cancer” AND “acute ovarian failure OR primary ovarian insufficiency” AND “risk”. Five publications were considered for further review as they described acute ovarian failure as an independent condition without grouping patients in a broader premature menopause category. Although high-dose pelvic radiotherapy, haematopoietic stem-cell transplantation, and alkylating chemotherapy have been identified as risk factors associated with acute ovarian failure, clinicians do not have a tool that accurately estimates the risk of acute ovarian failure for individual paediatric patients with cancer at the time of cancer diagnosis. We did not find any study that aimed to develop risk estimates of acute ovarian failure for individual paediatric patients with cancer at the time of cancer diagnosis.

Added value of this study

To our knowledge, we have developed and validated the first models for predicting the risk of acute ovarian failure in female survivors of childhood cancer. Although physicians are aware of the gonadotoxic treatment exposures with a high likelihood of causing acute ovarian failure, there are no available prediction tools to estimate the risk of acute ovarian failure for a given patient on the basis of a planned oncological treatment regimen. A precise risk estimate available to clinicians will guide informed discussions with patients and their families for time-sensitive interventions to preserve fertility function before initiation of cancer treatment and inform the need for future ovarian hormone replacement treatment after completion of cancer therapy. We provide an easily accessible and user-friendly online calculator for acute ovarian failure risk for clinicians to directly calculate each patient's risk for acute ovarian failure on the basis of their planned cancer treatment. The developed models performed well both internally and externally, highlighting the validity of the risk estimates and ensuring that clinical recommendations are provided with confidence.

Implications of all the available evidence

Since most patients with childhood cancer will become long-term survivors, the focus of cancer survivorship research has shifted toward maximising survivor quality of life. Our models and the associated web application can help inform discussions with female patients and their families at the time of cancer diagnosis regarding the need for fertility preservation before cancer treatment and the possible need for ovarian hormone replacement after completion of cancer therapy.

Girls are born with a finite supply of ovarian follicles that decline with age.7 Cancer-directed therapies, such as radiotherapy and alkylating chemotherapy, can accelerate this decline, resulting in early cessation of ovarian endocrine and reproductive function.7 Primary ovarian insufficiency is defined as compromised gonadal function before the age of 40 years.8 Primary ovarian insufficiency can manifest as acute ovarian failure or premature menopause. Acute ovarian failure occurs when an individual permanently stops menstruating within 5 years of their cancer diagnosis, does not progress through puberty, or does not achieve menarche by 18 years of age following cancer treatment.9 Previous investigations from the Childhood Cancer Survivor Study (CCSS) have shown a 6% prevalence of acute ovarian failure in female survivors of childhood cancer.9 Premature menopause occurs when ovarian function is retained for at least 5 years following cancer diagnosis, but non-surgical menopause develops before the survivor reaches 40 years of age.10 In the general population, the prevalence of premature, non-surgical menopause is approximately 1%,11 whereas the cumulative incidence of premature menopause (excluding acute ovarian failure) reported in female survivors from the CCSS cohort is 9% by the age of 40 years.10 Acute ovarian failure and premature menopause can restrict reproductive options, reduce quality of life, increase anxiety and depressive feelings, and increase the risk for serious morbidities including ischaemic heart disease, osteoporosis, and cognitive decline.10, 12, 13, 14, 15

Improved precision in predicting an individual's risk for developing primary ovarian insufficiency can facilitate appropriate counselling and fertility preservation at the time of cancer diagnosis and be used to evaluate the need for future hormone replacement therapies. Obtaining an accurate risk estimate is important because available fertility preservation technologies such as cryopreservation of ovarian tissue and oocytes are expensive and invasive. Ovarian tissue cryopreservation requires surgery, the potential for future livebirths is poorly established, and there is concern that some malignancies might involve the ovary, precluding reimplantation of the tissue. The operative risk might be increased in children who are immunocompromised or have abnormal blood counts, which increases their risk for infection or bleeding. Oocyte harvest can only be offered to post-pubertal girls and women, and ovarian hyperstimulation can require up to 4–6 weeks before oocytes can be retrieved,16 which impedes the use of harvesting before gonadotoxic treatment is initiated. No studies have addressed the safety or success rate of these procedures in children and adolescents.17, 18

Although physicians are aware of the gonadotoxic treatment exposures that are likely to cause acute ovarian failure, no prediction tools are available to estimate the acute ovarian failure risk for a given patient on the basis of a planned oncological treatment regimen. To address this gap, we developed and externally validated risk prediction models for clinical use. Our goal was to focus on risk prediction of acute ovarian failure at the time of cancer diagnosis to inform clinicians of the need for time-sensitive interventions. By offering fertility preservation procedures before treatment initiation to patients at a substantial risk of acute ovarian failure, the opportunity for future reproduction in this group can be maximised, and the risk of performing unnecessary procedures on patients at low risk of acute ovarian failure can be minimised.

Section snippets

Study design and participants

The CCSS, a multi-institutional longitudinal cohort study of 24 362 survivors of childhood cancer from the USA and Canada, was the primary data source for this study. Established in 1994, its cohort characteristics, eligibility criteria, and study design features have been documented elsewhere.19, 20 Briefly, the cohort includes 5-year survivors diagnosed before the age of 21 years with an eligible cancer type (leukaemia, CNS cancers, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms' tumour,

Results

Data were collected for participants in the CCSS cohort followed up between Nov 3, 1992, and Nov 25, 2016, and for participants in the SJLIFE cohort followed up between Oct 17, 2007, and April 16, 2012. Of the total 11 336 female CCSS participants identified, 5450 (48·1%) were excluded (figure 1). 8770 (77·4%) participants had ovarian status information, and 5886 (51·9%) participants met all eligibility criteria and were included in the analysis. Of the 1644 total female survivors in the SJLIFE

Discussion

With AUC values ranging from 0·78 to 0·82 in the CCSS cohort and 0·94 to 0·96 in the external validation using the SJLIFE cohort, we have developed, to our knowledge, the first risk prediction models for acute ovarian failure that provide a high level of confidence appropriate for use in a clinical setting. Because AP values larger than the population event rate imply superior predictive ability to detect cases of acute ovarian failure, values for the prescribed dose and ovarian dose models

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