A 30-year-old woman presents with a history of no menses since she stopped taking oral contraceptives 6 months ago in order to conceive. She had undergone puberty that was normal in both timing and development, with menarche at 12 years of age. At 18 years of age, she started taking oral contraceptives for irregular menses. She reports stress at work. Her weight is 59 kg, and her height 1.66 m; her body-mass index (the weight in kilograms divided by the square of the height in meters) is 21.3. There is no galactorrhea, hirsutism, or acne. The pelvic examination is normal, a pregnancy test is negative, the prolactin level is normal, and the follicle-stimulating hormone (FSH) level is in the menopausal range. How should she be evaluated and treated?

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Primary Ovarian Insufficiency

Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the 1970s with the broader introduction of multimodality approaches, often including combination chemotherapy with or without radiation therapy. With this increase in rates of survivorship has come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research initiative designed to establish a large and extensively characterized cohort of more than 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This ongoing study, which reflects the single most comprehensive body of information ever assembled on childhood and adolescent cancer survivors, provides a dynamic framework and resource to investigate current and future questions about childhood cancer survivors.

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The Childhood Cancer Survivor Study: A National Cancer Institute–Supported Resource for Outcome and Intervention Research

The number of long-term cancer survivors (> or =5 years after diagnosis) in the U.S. continues to rise, with more than 10 million Americans now living with a history of cancer. Along with such growth has come increasing attention to the continued health problems and needs of this population. Many cancer survivors return to normal functioning after the completion of treatment and are able to live relatively symptom-free lives. However, cancer and its treatment can also result in a wide range of physical and psychological problems that do not recede with time. Some of these problems emerge during or after cancer treatment and persist in a chronic, long-term manner. Other problems may not appear until months or even years later. Regardless of when they present, long-term and late effects of cancer can have a negative effect on cancer survivors' quality of life. This article describes the physical and psychological long-term and late effects among adult survivors of pediatric and adult cancers. The focus is on the prevalence and correlates of long-term and late effects as well as the associated deficits in physical and emotional functioning. In addition, the emergence of public health initiatives and large-scale research activities that address the issues of long-term cancer survivorship are discussed. Although additional research is needed to fully understand and document the long-term and late effects of cancer, important lessons can be learned from existing knowledge. Increased awareness of these issues is a key component in the development of follow-up care plans that may allow for adequate surveillance, prevention, and the management of long-term and late effects of cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.23448

Physical and psychological long-term and late effects of cancer

The increasing number of young survivors of cancer who have favorable outcomes necessitates planning for the preservation of fertility, which may mean modifying the strategy for oncologic treatment. In addition to in vitro fertilization in women and sperm banking in men, new methods on the horizon include in vitro follicle maturation and techniques for tissue transplantation.

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Preservation of Fertility in Patients with Cancer

These studies were undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on ovarian function and reproductive outcomes. We reviewed the frequency of acute ovarian failure, premature menopause, live birth, stillbirth, spontaneous and therapeutic abortion and birth defects in the participants in the Childhood Cancer Survivor Study (CCSS). Acute ovarian failure (AOF) occurred in 6.3% of eligible survivors. Exposure of the ovaries to high-dose radiation (especially over 10 Gy), alkylating agents and procarbazine, at older ages, were significant risk factors for AOF. Premature nonsurgical menopause (PM) occurred in 8% of participants versus 0.8% of siblings (rate ratio = 13.21; 95% CI, 3.26 to 53.51; P < .001). Risk factors for PM included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score, and a diagnosis of Hodgkin's lymphoma. One thousand two hundred twenty-seven male survivors reported they sired 2,323 pregnancies, and 1,915 female survivors reported 4,029 pregnancies. Offspring of women who received uterine radiation doses of more than 5 Gy were more likely to be small for gestational age (birthweight < 10 percentile for gestational age; 18.2% v 7.8%; odds ratio = 4.0; 95% CI, 1.6 to 9.8; P = .003). There were no differences in the proportion of offspring with simple malformations, cytogenetic syndromes, or single-gene defects. These studies demonstrated that women treated with pelvic irradiation and/or increasing alkylating agent doses were at risk for acute ovarian failure, premature menopause, and small-for-gestational-age offspring. There was no evidence for an increased risk of congenital malformations. Survivors should be generally reassured although some women have to consider their potentially shortened fertile life span in making educational and career choices.

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Ovarian Failure and Reproductive Outcomes After Childhood Cancer Treatment: Results From the Childhood Cancer Survivor Study

Background: Childhood cancer survivors who retain ovarian function after completing cancer treatment are at increased risk of developing premature menopause, defi ned as cessation of menses before age 40 years. However, published data pertaining to the risk and frequency of premature menopause are limited. Methods: We assessed the incidence of and risk factors for premature menopause in 2819 survivors of childhood cancer who were older than 18 years and were participants in the multicenter Childhood Cancer Survivor Study (CCSS). The comparison group was 1065 female siblings of participants in the CCSS. A multiple Poisson regression model was constructed to determine risk factors for nonsurgical premature menopause. All statistical tests were twosided. Results: A total of 126 childhood cancer survivors and 33 control siblings developed premature menopause. Of these women, 61 survivors (48%) and 31 siblings (94%) had surgically induced menopause (rate ratio [RR] = 0.8, 95% confi dence interval [CI] = 0.52 to 1.23). However, the cumulative incidence of nonsurgical premature menopause was higher for survivors than for siblings (8% versus 0.8%; RR = 13.21, 95% CI = 3.26 to 53.51; P <.001). A multiple Poisson regression model showed that risk factors for nonsurgical premature menopause included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score (based on number of alkylating agents and cumulative dose), and a diagnosis of Hodgkin lymphoma. For survivors who were treated with alkylating agents plus abdominopelvic radiation, the cumulative incidence of nonsurgical premature menopause approached 30%. Conclusions: The results of this study will facilitate counseling current survivors about their future risk of premature menopause and aid in designing new regimens that seek to diminish late ovarian toxicity. [J Natl Cancer Inst 2006;98: 890 – 6 ]

Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study.

Bone density in survivors of childhood cancer.

Telemedicine can potentially meet objectives of long-term follow-up care (LTFU) for childhood cancer survivors (CCS) while reducing barriers. We surveyed providers at our institution about their satisfaction with video-conference virtual visits (VV) with 81 CCS during COVID-19 restrictions. The same 81 CCS (or parent proxies) were surveyed about their experience, of which 47% responded. Providers and CCS were highly satisfied with VV (86% and 95% "completely/very satisfied," respectively). CCS rated VV "as/nearly as" helpful as in-person visits (66%) and 82% prefer VV remain an option postpandemic. High levels of survivor and provider satisfaction with VV support ongoing investigation into implementation for LTFU.

Virtual visits as long-term follow-up care for childhood cancer survivors: Patient and provider satisfaction during the COVID-19 pandemic.

DESIGN AND INTERVENTION This was an evaluation of participants enrolled in LESS (Late Effects Surveillance System), a prospective, multicenter study of pediatric patients who had received radiotherapy and/or chemotherapy for primary Ewing’s sarcoma, osteosarcoma or soft-tissue sarcoma. Exclusion criteria included age >21 years at diagnosis, previous history of thyroid dysfunction, thyroidec tomy during treatment for sarcoma, stem cell trans plantation, and tumor progression. Thyroid function tests were performed within 4 weeks of cancer therapy cessation, and annually thereafter in patients who had received head and/or neck irradiation. Dietary iodine intake was not evaluated.

Jean E Mulder

Papers

Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study.

Bone density in survivors of childhood cancer.

Virtual visits as long-term follow-up care for childhood cancer survivors: Patient and provider satisfaction during the COVID-19 pandemic.

Thyroid late effects after treatment of childhood sarcoma