Factors influencing risk-based care of the childhood cancer survivor in the 21st century.

The population of adult survivors of childhood cancer continues to grow as survival rates improve. Although it is well established that these survivors experience various complications and comorbidities related to their malignancy and treatment, this risk is modified by many factors that are not directly linked to their cancer history. Research evaluating the influence of patient-specific demographic and genetic factors, premorbid and comorbid conditions, health behaviors, and aging has identified additional risk factors that influence cancer treatment-related toxicity and possible targets for intervention in this population. Furthermore, although current long-term follow-up guidelines comprehensively address specific therapy-related risks and provide screening recommendations, the risk profile of the population continues to evolve with ongoing modification of treatment strategies and the emergence of novel therapeutics. To address the multifactorial modifiers of cancer treatment-related health risk and evolving treatment approaches, a patient-centered and risk-adapted approach to care that often requires a multidisciplinary team approach, including medical and behavioral providers, is necessary for this population. CA Cancer J Clin 2018;68:133-152. © 2018 American Cancer Society.

Primary hypothyroidism in childhood cancer survivors: Prevalence, risk factors, and long-term consequences.

BACKGROUND: Data on primary hypothyroidism and its long-term impact on the health, cognition, and quality of life (QOL) of childhood cancer survivors are limited. This study examined the prevalence of and risk factors for primary hypothyroidism and its associations with physical, neurocognitive, and psychosocial outcomes. METHODS: This was a retrospective study with a cross-sectional health outcome analysis of an established cohort comprising 2965 survivors of childhood cancer (52.8% male; median current age, 30.9 years, median time since cancer diagnosis, 22.3 years). Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between primary hypothyroidism and cancer-related risk factors, cardiovascular disease risk factors, frailty, neurocognitive and QOL outcomes, social attainment, and subsequent thyroid carcinoma. Associations between serum free thyroxine and thyrotropin levels at assessment and health outcomes were explored. RESULTS: The prevalence of primary hypothyroidism was 14.7% (95% CI, 13.5%-16.0%). It was more likely in females (OR, 1.06; 95% CI, 1.03-1.08), was less likely in non-Whites (OR, 0.96; 95% CI, 0.93-0.99), was associated with thyroid radiotherapy (higher risk at higher doses), and was more common if cancer was diagnosed at an age ≥ 15.0 years versus an age < 5 years (OR, 1.05; 95% CI, 1.01-1.09). Primary hypothyroidism was associated with frailty (OR, 1.54; 95% CI, 1.05-2.26), dyslipidemia (OR, 1.52; 95% CI, 1.14-2.04), impaired physical QOL (OR, 1.66; 95% CI, 1.12-2.48), and having health care insurance (OR, 1.51; 95% CI, 1.07-2.12). CONCLUSIONS: Primary hypothyroidism is common in survivors and is associated with unfavorable physical health and QOL outcomes. The impact of thyroid hormone replacement practices on these outcomes should be investigated further.

Neighborhood effect and obesity in adult survivors of pediatric cancer: A report from the St. Jude lifetime cohort study.

Survivors of childhood cancer are at risk for obesity, a condition potentially modifiable if dietary intake and physical activity are optimized. These health behaviors are likely influenced by neighborhood of residence, a determinant of access to healthy, affordable food and safe and easy exercise opportunities. We examined associations between neighborhood level factors and obesity among survivors in the St. Jude Lifetime cohort and community comparison group members. Persons with residential addresses available for geocoding were eligible for analysis (n = 2,265, mean age 32.5 [SD 9.1] years, 46% female, 85% white). Survivors completed questionnaires regarding individual behaviors; percent body fat was assessed via dual X-ray absorptiometry (obesity: ≥25% males; ≥35% females); neighborhood effect was characterized using census tract of residence (e.g., neighborhood socioeconomic status [SES], rurality). Structural equation modeling was used to determine associations between neighborhood effect, physical activity, diet, smoking, treatment exposures and obesity. Obese survivors (n = 1,420, 62.7%) were more likely to live in neighborhoods with lower SES (RR: 1.23, 95% CI: 1.10-1.38) and rural areas (RR: 1.22, 95% CI: 1.07-1.39) compared to survivors with normal percent body fat. Resource-poor neighborhoods (standardized effect: 0.06, p < 0.001) and cranial radiation (0.16, p < 0.001) had direct effects on percent body fat. Associations between neighborhood of residence and percent body fat were increased (0.01, p = 0.04) among individuals with a poor diet. Neighborhoods where survivors reside as an adult is associated with obesity. Interventions targeting survivors should incorporate strategies that address environmental influences on obesity.

Psychosexual Functioning of Female Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort Study.

INTRODUCTION: There is a growing population of childhood cancer survivors at risk for adverse outcomes, including sexual dysfunction. AIM: To estimate the prevalence of and risk factors for sexual dysfunction among adult female survivors of childhood cancer and evaluate associations between dysfunction and psychological symptoms/quality of life (QOL). METHODS: Female survivors (N = 936, mean 7.8 ± 5.6 years at diagnosis; 31 ± 7.8 years at evaluation) and noncancer controls (N = 122) participating in the St. Jude Lifetime Cohort Study completed clinical evaluations, Sexual Functioning Questionnaires (SFQ), and Medical Outcomes Survey Short Forms 36 (SF-36). Linear models compared SFQ scores between sexually active survivors (N = 712) and controls; survivors with scores <10th percentile of controls were classified with sexual dysfunction. Logistic regression evaluated associations between survivor characteristics and sexual dysfunction, and between sexual dysfunction and QOL. OUTCOMES: Sexual dysfunction was defined by scores <10th percentile of noncancer controls on the SFQ overall, as well as the domains of arousal, interest, orgasm, and physical problems, while QOL was measured by scores on the SF-36 with both physical and mental summary scales. RESULTS: Sexual dysfunction was prevalent among 19.9% (95% CI 17.1, 23.1) of survivors. Those diagnosed with germ cell tumors (OR = 8.82, 95% CI 3.17, 24.50), renal tumors (OR = 4.49, 95% CI 1.89, 10.67), or leukemia (OR = 3.09, 95% CI 1.50, 6.38) were at greater risk compared to controls. Age at follow-up (45-54 vs 18-24 years; OR = 5.72, 95% CI 1.87, 17.49), pelvic surgery (OR = 2.03, 95% CI 1.18, 3.50), and depression (OR = 1.96, 95% CI 1.10, 3.51) were associated with sexual dysfunction. Hypogonadism receiving hormone replacement (vs nonmenopausal/nonhypogonadal; OR = 3.31, 95% CI 1.53, 7.15) represented an additional risk factor in the physical problems (eg, vaginal pain and dryness) subscale. Survivors with sexual dysfunction, compared to those without sexual dysfunction, were more likely to score <40 on the physical (21.1% vs 12.7%, P = .01) and mental health (36.5% vs 18.2%, P < .01) summary scales of the SF-36. Only 2.9% of survivors with sexual dysfunction reported receiving intervention. CLINICAL IMPLICATIONS: Health care providers should be aware of the increased risk of sexual dysfunction in this growing population, inquire about symptomology, and refer for appropriate intervention. STRENGTHS & LIMITATIONS: Strengths of this study include the use of a validated tool for evaluating sexual function in a large population of clinically assessed female childhood cancer survivors. Limitations include potential for selection bias, and lack of clinically confirmed dysfunction. CONCLUSION: Sexual dysfunction is prevalent among female childhood cancer survivors and few survivors receive intervention; further research is needed to determine if those with sexual dysfunction would benefit from targeted interventions. Bjornard KL, Howell CR, Klosky JL, et al. Psychosexual Functioning of Female Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort Study. J Sex Med 2020;17:1981-1994.

Fertility-related services in pediatric oncology across the cancer continuum: a clinic overview.

PURPOSE: Fertility-related services in pediatric oncology are increasing, but barriers to care remain and few structured programs are described in the literature. Therefore, the study objectives were (1) to characterize fertility-related services in a large pediatric oncology center and (2) to discuss recommendations for fertility-related services across the pediatric cancer continuum. METHODS: Medical records of all cases referred to our Fertility Preservation Clinic within a 3-year period were reviewed, which included 292 patients/survivors with malignant disease. Approximately half (n = 152/292, 52.1%) were cancer patients referred prior to treatment (n = 92/152) or while on active therapy (n = 60/152). The other half (n = 140/292; 47.9%) were survivors who had completed treatment. RESULTS: Referrals more than doubled over 3 years. Most patients referred before treatment were offered and opted for FP (72.8% attempted; 58.9% completed). More male than female patients opted for FP (77.6% vs. 22.4%), but completion rates were higher among females (93.3% vs. 76.9%). Rates of FP before treatment did not increase over time (p = .752). Many patients on-treatment were referred for infertility risk counseling, demonstrating information/support needs in this group. Referred survivors questioned their fertility post-treatment and completed fertility assessments, indicating intact fertility among few (~ 15%). CONCLUSIONS: This review demonstrated the acceptance and increasing need for fertility-related services in pediatric oncology across the cancer continuum, including FP before treatment, counseling during treatment, and fertility assessment in survivorship. Based on our experiences, current recommendations are discussed and include standardized procedures, streamlined referrals, adequate communication/education (of providers and families), and meeting specific needs of young cancer patients/survivors.

Long-term survivors of childhood, adolescent and young adult non-Hodgkin lymphoma.

Progress in overall survival rates for childhood non-Hodgkin lymphoma (NHL) can be largely attributed to effective development and conduct of a number of international treatment studies. Knowledge gained from these studies has shifted the treatment paradigm from a "one-size fits all" strategy to a histologically dependent approach. More specifically, many now adhere to a risk-stratified approach, prescribing cumulative doses and intensities of chemotherapeutic exposures based upon the aggressiveness of disease. Moreover, recognition that high cure rates could be achieved without the use of radiation has eliminated the use of this modality in frontline settings for the majority of newly diagnosed children. These changes have contributed to the emergence of a heterogeneous group of NHL survivors. As the number of NHL survivors continues to increase, providers will encounter a wide spectrum of individuals whose risk for long-term complications are accordingly diverse. The following review summarizes the existing literature surrounding late effects, such as chronic health conditions, functional and neurocognitive performance outcomes, and health-related quality of life, that are unique to NHL survivors, as well as those extrapolated from the broader childhood cancer survivor population.

Two-year-old female with EBV-positive diffuse large B-cell lymphoma and subsequent CNS involvement with neurolymphomatosis.

We describe a case of Epstein-Barr virus (EBV) positive, diffuse large B-cell lymphoma in a 2-year-old female who went on to develop relapsed/refractory central nervous system (CNS) disease, manifesting as cranial nerve neurolymphomatosis. Although her atypical presentation was thought to be associated with an immune deficiency, extensive work-up was negative. Despite subsequent treatment with third-party EBV-specific cytotoxic T-lymphocytes, she died of progressive disease. This case report raises questions as to whether tailored treatment approaches should be considered for atypical presentations of pediatric lymphoma (e.g., CNS and virus-associated).

Websites about, not for, adolescents? A systematic analysis of online fertility preservation information for adolescent and young adult cancer patients.

PURPOSE: Fertility preservation is an increasingly important topic in adolescent and young adult cancer survivorship, yet treatments remain under-utilized, possibly due to lack of awareness and understanding. The internet is widely used by adolescents and young adults and has been proposed to fill knowledge gaps and advance high-quality, more equitable care. As a first step, this study analyzed the quality of current fertility preservation resources online and identified opportunities for improvement. METHODS: We conducted a systematic analysis of 500 websites to assess the quality, readability, and desirability of website features, and the inclusion of clinically relevant topics. RESULTS: The majority of the 68 eligible websites were low quality, written at college reading levels, and included few features that younger patients find desirable. Websites mentioned more common fertility preservation treatments than promising experimental treatments, and could be improved with cost information, socioemotional impacts, and other equity-related fertility topics. CONCLUSIONS: Currently, the majority of fertility preservation websites are about, but not for, adolescent and young adult patients. High-quality educational websites are needed that address outcomes that matter to teens and young adults, with a priority on solutions that prioritize equity. IMPLICATIONS FOR CANCER SURVIVORS: Adolescent and young adult survivors have limited access to high-quality fertility preservation websites that are designed for their needs. There is a need for the development of fertility preservation websites that are clinically comprehensive, written at appropriate reading levels, inclusive, and desirable. We include specific recommendations that future researchers can use to develop websites that could better address AYA populations and improve the fertility preservation decision making process.

Trends in physical functioning in acute lymphoblastic leukemia and non-Hodgkin lymphoma survivors across three decades.

PURPOSE: The impact of changes in therapy for childhood acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) on the prevalence of physical performance limitations and participation restrictions among survivors is unknown. We aimed to describe the prevalence of reduced function among ALL and NHL survivors by treatment era. METHODS: Participants included survivors of childhood ALL and NHL, and a cohort of their siblings, participating in the Childhood Cancer Survivor Study (CCSS). Physical function was measured using questionnaire. The prevalence of reduced function was compared to siblings using generalized estimating equations, overall and stratified by treatment decade. Associations between organ system-specific chronic conditions (CTCAE v4.03) and function were also evaluated. RESULTS: Among 6511 survivors (mean age 25.9 years (standard deviation 6.5)) and 4127 siblings, risk of performance limitations (15.2% vs. 12.5%, prevalence ratio [PR] = 1.5, 95%CI = 1.3-1.6), restrictions in personal care (2.0% vs. 0.6%, PR = 3.1, 95% CI = 2.0-4.8), routine activities (5.5% vs. 1.6%, PR = 3.6, 95% CI = 2.7-4.8), and work/school attendance (8.8% vs. 2.1%, PR = 4.5, 95% CI = 3.6-5.7) was increased in survivors vs. siblings. The prevalence of survivors reporting reduced function did not decrease between the 1970s and 1990s. The presence of neurological and cardiovascular conditions was associated with reduced function regardless of treatment decade. CONCLUSIONS: Despite changes in therapy, the prevalence of poor physical function remained constant between the 1970s and 1990s. The CCSS clinical trial registration number is NCT01120353 (registered May 6, 2010). IMPLICATIONS FOR CANCER SURVIVORS: Our findings support screening for reduced physical function so that early interventions to improve physical performance and mitigate chronic disease can be initiated.

Hypothalamic-Pituitary Disorders in Childhood Cancer Survivors: Prevalence, Risk Factors and Long-Term Health Outcomes.

CONTEXT: Data on hypothalamic-pituitary (HP) disorders in systematically evaluated childhood cancer survivors are limited. OBJECTIVE: To describe prevalence, risk factors, and associated adverse health outcomes of deficiencies in GH deficiency (GHD), TSH deficiency (TSHD), LH/FSH deficiency (LH/FSHD), and ACTH deficiency (ACTHD), and central precocious puberty (CPP). DESIGN: Retrospective with cross-sectional health outcomes analysis. SETTING: Established cohort; tertiary care center. PATIENTS: Participants (N = 3141; median age, 31.7 years) were followed for a median 24.1 years. MAIN OUTCOME MEASURE: Multivariable logistic regression was used to calculate ORs and 95% CIs for associations among HP disorders, tumor- and treatment-related risk factors, and health outcomes. RESULTS: The estimated prevalence was 40.2% for GHD, 11.1% for TSHD, 10.6% for LH/FSHD, 3.2% for ACTHD, and 0.9% for CPP among participants treated with HP radiotherapy (n = 1089), and 6.2% for GHD, and <1% for other HP disorders without HP radiotherapy. Clinical factors independently associated with HP disorders included HP radiotherapy (at any dose for GHD, TSHD, LH/FSHD, >30 Gy for ACTHD), alkylating agents (GHD, LH/FSHD), intrathecal chemotherapy (GHD), hydrocephalus with shunt placement (GHD, LH/FSHD), seizures (TSHD, ACTHD), and stroke (GHD, TSHD, LH/FSHD, ACTHD). Adverse health outcomes independently associated with HP disorders included short stature (GHD, TSHD), severe bone mineral density deficit (GHD, LH/FSHD), obesity (LH/FSHD), frailty (GHD), impaired physical health-related quality of life (TSHD), sexual dysfunction (LH/FSHD), impaired memory, and processing speed (GHD, TSHD). CONCLUSION: HP radiotherapy, central nervous system injury, and, to a lesser extent, chemotherapy are associated with HP disorders, which are associated with adverse health outcomes.

Peripheral neuropathy in children and adolescents treated for cancer.

Peripheral neuropathy is a well recognised treatment-related toxicity in children with cancer, associated with exposure to neurotoxic chemotherapy agents. Acute damage can occur in sensory, motor, or autonomic neurons, with symptoms that are rarely life threatening, but often severe enough to interfere with function during therapy and after treatment ends. The type of neuropathy and specific symptoms are associated with multiple factors including age at time of therapy, genetic predisposition, chemotherapy type and cumulative dose, and exposure to other agents during therapy. In this Review, we describe the peripheral neuropathy phenotype in children during cancer therapy and among survivors who have completed therapy, to summarise genetic and treatment-related risk factors for neuropathy, and to outline strategies to monitor and detect neuropathy during and after therapy. Additionally, we outline strategies for medical management of neuropathy during treatment and potential rehabilitation interventions to prevent or remediate functional loss.

Frailty and quality of life in adult survivors of childhood cancer.

INTRODUCTION: Adult survivors of childhood cancer are at risk for frailty, a state of diminished physiologic reserve, typically seen in older adults, associated with morbidity and mortality. They are also at risk for poor quality of life. This review explores potential associations between frailty and quality of life and proposes potential interventions that may prevent or remediate frail health. AREAS COVERED AND LITERATURE SEARCH: A literature search using MEDLINE and EMBASE was undertaken using key words: childhood cancer survivors and each of the following: frailty, physical performance, emotional health, and quality of life. 796 abstracts were reviewed for relevance. Reference lists for retrieved articles were consulted for pertinent manuscripts (N=40). Recent literature (from January 2013 to November 2016) was obtained using the key words: aging and frailty and quality of life. The final reference list includes 44 documents. EXPERT OPINION: Childhood cancer survivors are at risk for frailty and less than optimal quality of life. Poor emotional health may contribute to this association. Further research is needed to better explain these associations and to provide a foundation for the development of interventions designed to prevent and remediate frail health and suboptimal quality of life in this population.