Gonadal Function and Fertility Among Survivors of Childhood Cancer

Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration.

This chapter begins with a basic science update on the development of the female reproductive system. This starts with sections on maturation of the neuroendocrine-ovarian axis and regulation of the neuroendocrine-ovarian axis. The former reviews maturation of the hypothalamic-pituitary-ovarian axis during fetal life, infancy and childhood, and adolescence, concluding with mechanisms that underlie the normal adult ovulatory cycle. The regulation section reviews factors controlling the onset of puberty, regulation of gonadotropin secretion, and regulation of ovarian secretion. Following are successive sections on adrenarche and the regulation of adrenal androgen secretion and hormonal secretion, transport, metabolism, and mechanisms of action, the latter covering both peptide and steroid hormones. The basic science update concludes with a review of the maturation of sex hormone target organs covering both the classical and nonclassical effects of sex steroids on their targets.

The normal hormonal and sexual maturational changes that culminate in sexual maturity are then detailed from fetal life through the adult menstrual cycle. This section concludes with a discussion of the common normal pubertal variants, including premature thelarche, premature pubarche, constitutional delay of growth and pubertal development, and physiological adolescent anovulation.

The last half of the chapter reviews the causes, differential diagnosis, and management of abnormal puberty. The topics covered include precocious puberty, hypogonadism, and nonhypoestrogenic menstrual disturbances, such as hypothalamic anovulation and ovulatory dysfunction as a cause of dysfunctional uterine bleeding. The section concludes with a review of hyperandrogenism in adolescence, emphasizing the most common cause, polycystic ovary syndrome.

Treatments for childhood cancer have evolved over the past 50 years, with the goal of maximising the proportion of patients who achieve long-term survival, while minimising the adverse effects of therapy. We aimed to assess incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment.

We used data from the Childhood Cancer Survivor Study, a retrospective cohort with longitudinal follow-up of 5-year survivors of common childhood cancers (leukaemia, tumours of the CNS, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumour, neuroblastoma, soft tissue sarcoma, or bone tumours) who were diagnosed before the age of 21 years and from 1970 to 1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. We used multivariable regression models to estimate hazard ratios per diagnosis decade, and we added treatment variables to assess whether treatment changes attenuated associations between diagnosis decade and chronic disease risk.

Among 23 601 survivors with a median follow-up of 21 years (IQR 15–25), the 20-year cumulative incidence of at least one grade 3–5 chronic condition decreased significantly from 33·2% (95% CI 32·0–34·3) in those diagnosed 1970–79 to 29·3% (28·4–30·2; p<0·0001) in 1980–89, and 27·5% (26·4–28·6; p=0·012 vs 1980–89) in 1990–99. By comparison, the 20-year cumulative incidence of at least one grade 3–5 condition in 5051 siblings was 4·6% (95% CI 3·9–5·2). The 15-year cumulative incidence of at least one grade 3–5 condition was lower for survivors diagnosed 1990–99 compared with those diagnosed 1970–79 for Hodgkin lymphoma (17·7% [95% CI 15·0–20·5] vs 26·4% [23·8–29·1]; p<0·0001), non-Hodgkin lymphoma (16·9% [14·0–19·7] vs 23·8% [19·9–27·7]; p=0.0053), astrocytoma (30·5% [27·8–33·2] vs 47·3% [42·9–51·7]; p<0·0001), Wilms tumour (11·9% [9·5–14·3] vs 17·6% [14·3–20·8]; p=0·034), soft tissue sarcoma (28·3% [23·5–33·1] vs 36·5% [31·5–41·4]; p=0·021), and osteosarcoma (65·6% [60·6–70·6] vs 87·5% [84·1–91·0]; p<0·0001). By contrast, the 15-year cumulative incidence of at least one grade 3–5 condition was higher (1990–99 vs 1970–79) for medulloblastoma or primitive neuroectodermal tumour (58·9% [54·4–63·3] vs 42·9% [34·9–50·9]; p=0·00060), and neuroblastoma (25·0% [21·8–28·2] vs 18·0% [14·5–21·6]; p=0·0045). Results were consistent with changes in treatment as a significant mediator of the association between diagnosis decade and risk of grade 3–5 chronic conditions for astrocytoma (HR per decade without treatment in the model = 0·77, 95% CI 0·64–0·92; HR with treatment in the model=0·89, 95% CI 0·72–1·11; p_mediation=0·0085) and Hodgkin lymphoma (HR without treatment=0·75, 95% CI 0·65–0·85; HR with treatment=0·91, 95% CI 0·73–1·12; p_mediation=0·024). Temporal decreases in 15-year cumulative incidence comparing survivors diagnosed 1970–79 to survivors diagnosed 1990–99 were noted for endocrinopathies (5·9% [5·3–6·4] vs 2·8% [2·5–3·2]; p<0·0001), subsequent malignant neoplasms (2·7% [2·3–3·1] vs 1·9% [1·6–2·2]; p=0·0033), musculoskeletal conditions (5·8% [5·2–6·4] vs 3·3% [2·9–3·6]; p<0·0001), and gastrointestinal conditions (2·3% [2·0–2·7] vs 1·5% [1·3–1·8]; p=0·00037), while hearing loss increased (3·0% [2·6–3·5] vs 5·7% [5·2–6·1]; p<0·0001).

Our results suggest that more recently treated survivors of childhood cancer had improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximise overall survival, while reducing risk of long-term adverse events. Continuing advances in cancer therapy offer promise of further reducing the risk of long-term adverse events in childhood cancer survivors. However, achieving long-term survival for childhood cancer continues to come at a cost for many survivors, emphasising the importance of long-term follow-up care for this population.

National Cancer Institute and the American Lebanese-Syrian Associated Charities.

Gonadal damage is a common consequence of treatment for pediatric malignancies. Nononcologic conditions may also utilize treatments with potential impact on fertility. Models for oncology fertility preservation programs have emerged and demonstrate that a multidisciplinary team approach can have a positive impact on referral patterns, appropriate risk counseling, and access to fertility preservation options. Expansion of programmatic breadth is needed, providing improved care to nonmalignant conditions where the disease itself may impact reproductive health or treatment modalities.

With support from the Department of Pediatrics Chair's Initiative, a multidisciplinary, hospital-wide Fertility Preservation Service was created at the Children's Hospital of Philadelphia. A centralized team provides fertility consults across the institution, allowing for risk-based counseling and facilitation of fertility preservation options (both standard care and experimental).

Team structure, consult process, and available fertility options for prepubertal and pubertal males and females are described. Preinitiative and postinitiative referral patterns were analyzed. Postinitiative referrals from divisions outside oncology more than doubled (34% vs. 15% at baseline).

A comprehensive model for fertility counseling provides accessible, high-value fertility preservation care to pediatric and young adult patients with a wide variety of diagnoses. A centralized point of contact ensures timely referrals and risk-based counseling and streamlines access to fertility preservation procedures.

El tratamiento de las neoplasias infantiles ha aumentado las tasas de supervivencia, pero también el riesgo de desarrollar complicaciones tardías, muchas de tipo endocrino. El objetivo de este estudio es describir las endocrinopatías que se presentan en los primeros años de seguimiento de las neoplasias infantiles y analizar las variables relacionadas con su aparición.

Estudio retrospectivo de los pacientes remitidos a Endocrinología Pediátrica tras el tratamiento de una neoplasia maligna. Como endocrinopatías se incluyeron las afecciones hormonales por exceso o por defecto y la obesidad de nueva aparición. Las evaluaciones clínicas y analíticas se realizaron semestralmente. Pruebas estadísticas: chi cuadrado y regresión logística múltiple.

Se incluyen 55 pacientes (26 mujeres) con una edad en el momento del diagnóstico del tumor (media ± desviación estándar) de 6,0 ± 4,4 años y un seguimiento de 6,8 ± 3,6 años. Se diagnosticaron 30 endocrinopatías en 26 pacientes (47,3%), de los que 17 eran mujeres (p = 0,01). Once adolescentes presentaron hipogonadismo primario (26,2%, a los 0,6 ± 0,5 años de seguimiento), relacionándose su aparición con la radioterapia pélvica (odds ratio ajustada [OR] 3,99, p = 0,005). Once pacientes presentaron algún trastorno hipofisario (20,0%, a los 5,2 ± 2,4 años tras el diagnóstico) en relación con radioterapia cerebral (OR 1,54, p = 0,039). Seis niños (10,9%) presentaron hipotiroidismo primario a los 3,2 ± 1,0 años de seguimiento. Dos niños desarrollaron obesidad.

Los niños supervivientes de neoplasias malignas presentan diversas endocrinopatías ya en los primeros años tras el tratamiento oncológico, por lo que la evaluación hormonal debe iniciarse precozmente y repetirse de forma periódica.

The treatment of childhood cancers has increased survival rates, but also the risk of sequelae, such as endocrine complications. The objective of this study is to evaluate the endocrine disorders in survivors of childhood malignant tumors within the first years after treatment and analyze the variables related to their appearance.

A retrospective medical record review of patients referred to pediatric endocrinology after treatment of malignancy. Outcome measures were frequency and types of endocrine dysfunction and new-onset obesity. Clinical and laboratory evaluations were performed every 6 months. Statistics tests were: chi square and multiple logistic regression.

Fifty five patients (26 women) were included with an age at diagnosis of tumour (mean ± standard deviation) 6.0 ± 4.4 years and followed up for 6.8 ± 3.6 years. Thirty endocrine disorders were diagnosed in 26 patients (47.3%), 17 women (P = .01). Eleven adolescents had primary hypogonadism (26.2% to 0.6 ± 0.5 years of follow-up) in relation to local irradiation (adjusted odds ratio [OR] 3.99, P = .005). Eleven patients had a pituitary disorder (20.0%) 5.2 ± 2.4 years after diagnosis in relation to brain irradiation (OR 1.54, P = .039). Six children (10.9%) had primary hypothyroidism from 3.2 ± 1.0 years of follow-up. Two children developed obesity.

Endocrine disorders are frequently seen within the first years after diagnosis of a childhood cancer, so hormonal evaluation should start early and be repeated periodically.