School of Public Health, University of Alberta, Edmonton, AB, Canada.
University of Pennsylvania Perelman School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Lancet Oncol. 2020 Mar;21(3):436-445. doi: 10.1016/S1470-2045(19)30818-6. Epub 2020 Feb 14.
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.
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]).
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.
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.
Canadian Institutes of Health Research, Women and Children's Health Research Institute, National Cancer Institute, and American Lebanese Syrian Associated Charities.
癌症治疗可能会导致性腺损伤。急性卵巢衰竭是指在癌症诊断后 5 年内卵巢功能永久丧失。我们旨在开发和验证风险预测工具，为癌症患儿提供准确的临床指导。
在这项队列研究中，使用美国和加拿大的合格女性参与者（来自儿童癌症幸存者研究 [CCSS] 队列）开发了急性卵巢衰竭风险预测模型，并在圣裘德终身队列研究（SJLIFE）中进行了验证。如果 CCSS 队列中的 5 年幸存者在最近一次随访时至少 18 岁，并且有完整的治疗暴露和充分的月经史（包括初潮年龄、当前月经状况、末次月经年龄和绝经病因）信息可用，则将其纳入研究。SJLIFE 队列中的参与者是至少 10 年的幸存者。如果参与者患有卵巢激素缺乏症、缺少暴露信息或卵巢状态不确定，则将其从预测分析中排除。急性卵巢衰竭的结局定义为癌症诊断后 5 年内卵巢功能永久丧失，或癌症治疗后 18 岁时仍无初潮。在 CCSS 队列中，使用逻辑回归、随机森林和支持向量机作为候选方法来开发风险预测模型。使用接收者操作特征曲线下的面积（AUC）和精度-召回曲线（平均精度 [AP；平均阳性预测值]）对内部（在 CCSS 队列中）和外部（在 SJLIFE 队列中）评估预测性能。
收集了 1992 年 11 月 3 日至 2016 年 11 月 25 日期间随访的 CCSS 队列参与者的数据，并收集了 2007 年 10 月 17 日至 2012 年 4 月 16 日期间随访的 SJLIFE 队列参与者的数据。在 11336 名 CCSS 女性参与者中，5886 名（51.9%）符合所有分析纳入标准。从 SJLIFE 队列中确定了 1644 名参与者，其中 875 名（53.2%）符合分析条件。在分析的 CCSS 参与者中，有 353 名（6.0%）发生了急性卵巢衰竭，在分析的 SJLIFE 参与者中，有 50 名（5.7%）发生了急性卵巢衰竭。CCSS 队列的总中位随访时间为 23.9 年（IQR 20.4-27.9），SJLIFE 队列的中位随访时间为 23.9 年（19.0-30.0）。三种候选方法（逻辑回归、随机森林和支持向量机）的结果相似，选择了使用逻辑回归的规定剂量模型和卵巢剂量模型。这两个模型中的常见预测因子是造血干细胞移植史、累积烷化剂剂量和癌症诊断年龄与造血干细胞移植之间的相互作用。在 SJLIFE 队列中进行的外部验证模型产生了 0.94（95%CI 0.90-0.98）的 AUC 和 0.68（95%CI 0.53-0.81）的 AP，用于卵巢剂量模型，以及 0.96（0.94-0.97）的 AUC 和 0.46（0.34-0.61）的 AP 用于规定剂量模型。在此基础上，开发了一种在线风险计算器，供临床使用。
这两种急性卵巢衰竭风险预测模型都表现良好。如果有卵巢辐射剂量学的信息，则首选卵巢剂量模型。如果需要进行生育力保护干预，这些模型以及在线风险计算器可以帮助临床医生对新诊断癌症的女孩和年轻女性进行讨论。
加拿大卫生研究院、妇女与儿童健康研究所、美国国立癌症研究所和美国黎巴嫩叙利亚援助协会。
