Diminished ovarian reserve in adolescent cancer survivors treated with heavy metal chemotherapy.

The extent to which heavy metal chemotherapy results in treatment-related ovarian damage is controversial. Anti-Mullerian hormone (AMH) levels measured more than 1 year after cancer therapy completion were abstracted from the medical records of 39 female survivors of childhood cancer aged 11 years and older, whose only gonadotoxic exposure was heavy metal chemotherapy. One-fifth of survivors who received cisplatin had AMH levels indicative of diminished ovarian reserve at last measurement. There was an observed clustering of low AMH in patients diagnosed in the peripubertal age range (i.e., 10-12 years). These findings may support a small, but present, risk of gonadal damage after heavy metal chemotherapy.

Self-reported late effect symptom clusters among young pediatric cancer survivors.

PURPOSE: Most survivors of childhood cancer experience subsequent chronic conditions but little is known about concurrent symptoms. This study seeks to identify late effect symptom clusters among young pediatric cancer survivors. METHODS: Survivors ≥ 18 or parents of survivors < 18 years enrolled in an institutional cohort study indicated (yes/no) if they experienced certain symptoms after treatment. The sample was randomly divided in half for exploratory factor analyses to identify symptom clusters followed by confirmatory factor analyses. Symptoms with ≥ 10% prevalence were included. Cluster structure generalizability across subgroups was examined using congruence coefficients. RESULTS: The sample included 579 survivors (74% non-Hispanic white, 45% leukemia, 12.8 ± 4.5 years at survey, 5.9 ± 3.5 years since therapy). Respondents averaged three symptoms. Three clusters were identified: (1) gastrointestinal: abdominal pain, diarrhea, constipation, nausea, vomiting (Cronbach's α = 0.74); (2) psychological: depression, anxiety, memory problems, anger management problems, sleep problems (α = 0.71); and (3) neurologic: problems walking, numbness/tingling, fatigue, back pain, chronic pain, weakness/inability to move legs (α = 0.71). Confirmatory factor analysis confirmed the three-cluster structure (standardized root mean square residual: 0.09; parsimonious goodness of fit: 0.96; Bentler-Bonett normed fit index: 0.95). The gastrointestinal and psychological clusters were generalizable across most subgroups while the neurologic cluster varied across age and race/ethnicity subgroups. CONCLUSION: Three distinct late effect symptom clusters were identified in young childhood cancer survivors with gastrointestinal and psychological clusters remaining relatively stable across subgroups. Future studies should focus on the characteristics of patients who experience these symptoms, especially those with high symptom burden, and the synergistic impact on quality of life.

Psychosocial Functioning Among Caregivers of Childhood Cancer Survivors Following Treatment Completion.

OBJECTIVE: To inform efforts to better support caregivers of children with cancer during the transition from treatment to survivorship, this study sought to characterize caregiver mental health-related quality of life (HRQOL) and anxiety, and examine the influence of family psychosocial risk and caregiver problem-solving on these outcomes. METHOD: Participants included 124 caregivers (child age M = 10.05 years; SD = 4.78), 12-19 months from the conclusion of cancer-directed treatment. Participants' self-reported mental HRQOL, anxiety, and problem-solving were compared with community norms using t-tests. Correlations and hierarchical multiple regressions examined the influence of psychosocial risk and problem-solving on caregiver mental HRQOL and anxiety. RESULTS: Overall, caregivers reported HRQOL and anxiety within normal limits. Caregivers also reported more adaptive patterns of problem-solving than community norms. Subsets of caregivers reported clinical levels of psychosocial risk (11%) and at-risk levels of mental HRQOL (2.5%) and anxiety (5.7%). Females reported greater anxiety than males. Psychosocial risk and negative problem orientation (NPO) were both related to poorer mental HRQOL and greater anxiety (r = .40-.51, p's < .001). Positive problem orientation related to better mental HRQOL and lower anxiety (r = .18-.21, p's < .05). Impulsivity/carelessness and avoidance were associated with greater anxiety (r = .19-.25, p's < .05). Only NPO accounted for additional variance in mental HRQOL and anxiety, over and above psychosocial risk and demographic characteristics. CONCLUSIONS: The majority of caregivers appear to be resilient and experience limited distress during the off therapy period. Targeting negative cognitive appraisals (NPO) through cognitive-behavioral therapy or problem-solving skills training may further improve caregiver psychosocial functioning.

Longitudinal Description of Gonadal Function in Sickle-cell Patients Treated With Hematopoietic Stem Cell Transplant Using Alkylator-based Conditioning Regimens.

OBJECTIVES: This study describes the hormone profiles for gonadal late effects after alkylator-based hematopoietic stem cell transplant (HSCT) regimens used for sickle-cell disease (SCD). METHODS: This is a retrospective chart review of subjects followed in the post-HSCT clinic for sickle-cell disease. Patient demographics, pubertal development, characteristics of pre-HSCT disease severity, treatment before HSCT, conditioning regimens, presence of graft versus host disease and follicle-stimulating hormone, anti-Müllerian hormone (AMH), luteinizing hormone and testosterone were abstracted from the medical record. RESULTS: Forty subjects (24 female individuals) with SCD were 9 (±4.3) years old at HSCT and 7.9 years (±5.6) from HSCT. At the time of transplant, 8% of female individuals and no male individuals were pubertal and 58% of female individuals and 38% of male individuals had been treated with hydroxyurea. Post-HSCT, all of the female individuals had diminished ovarian reserve on the basis of low AMH values and 10 of the pubertal female individuals (71%) had premature ovarian insufficiency defined as follicle-stimulating hormone >40 mIU/mL ×2. There was no ovarian recovery and AMH remained very low or undetectable up to 13 years post-HSCT. In male individuals, luteinizing hormone and testosterone levels were normal for age. CONCLUSIONS: Post-HSCT for SCD, all female individuals had diminished ovarian reserve and most female individuals had POI, whereas male individuals had normal testosterone hormone production.

User-centered design and enhancement of an electronic personal health record to support survivors of pediatric cancers.

PURPOSE: The objective of this article is to demonstrate how user-centered design theory and methods can be employed to develop and iteratively improve technologies to support survivors of childhood cancer. METHODS: Focus groups and structured interviews with young adult survivors of pediatric cancer (N = 3), parents (N = 11), and healthcare providers (N = 14) were conducted to understand their needs as potential users and the contexts in which they would use an electronic personal health record (PHR) for survivors, Cancer SurvivorLinkTM (https://cancersurvivorlink.org/). Usability evaluations were conducted to assess the functionality of the PHR using think aloud protocol with survivors/parents (N = 4) and focus groups with providers (N = 12). RESULTS: Major themes identified through the needs assessment guided design of the PHR, including (1) education about the lifelong healthcare needs of pediatric cancer survivors ("Learn"), (2) secure electronic storage for healthcare documents to direct long-term follow-up care ("Store"), and (3) communication functionality to allow sharing of health documents with healthcare providers ("Share"). Usability evaluations identified challenges with the PHR design, which informed site enhancements to improve PHR usefulness and ease of use including a registration wizard and healthcare provider directory. CONCLUSIONS: User-centered design methods informed iterative enhancements to an untethered, patient-controlled PHR to address usability barriers and meet the self-identified needs of survivors of childhood cancer and their providers.

Assessment of ovarian function in adolescents and young adults after childhood cancer treatment-How accurate are young adult/parent proxy-reported outcomes?

BACKGROUND: Providers often rely on self-reported ovarian function in adolescent and young adult (AYA)-aged childhood cancer survivors when making clinical decisions. This study described reported menstrual patterns and the agreement between respondent-reported and biochemical premature ovarian insufficiency (POI) in this population. PROCEDURE: This was a cross-sectional study of survivors (or their parent proxy) aged 13-21.9 years who received gonadotoxic therapy and were enrolled in a longitudinal health survey. Participants reported menstrual regularity, hormone-replacement therapy (HRT) use, and ovarian dysfunction. Respondent-reported POI was defined as the survivor taking HRT for ovarian failure or having been told she had ovarian failure. Biochemical POI was defined as follicle-stimulating hormone (FSH) level ≥40 mIU/mL. The agreement between respondent-reported and biochemical POI was determined using Cohen's kappa coefficient (κ) and analyzed by demographic and clinical factors. RESULTS: Among 182 AYA-aged survivors (72.5% non-Hispanic White, 46.7% leukemia survivors), 14.8% reported requiring HRT to have menses but 55.5% reported regular menses without HRT use. Among survivors with FSH measurements (n = 130), 17.7% reported POI whereas 18.5% had FSH ≥40 mIU/mL (κ = 0.66, sensitivity 70.8%, specificity 94.3%). The highest agreement between respondent-reported and biochemical POI was with young adult self-report (κ = 0.78) and survivors with >5 survivor clinic (κ = 0.83) and/or >5 endocrinologist (κ = 1.00) visits. CONCLUSIONS: The majority of AYA-aged survivors reported having regular menses without HRT support. The accuracy of respondent-reported POI increased with repeated survivor clinic or endocrinologist visits, highlighting the importance of continued education. Survivors must be informed about their ovarian function to enable them to advocate for their reproductive health.

Knowledge of Late Effects Risks and Healthcare Responsibility in Adolescents and Young Adults Treated for Childhood Cancer.

OBJECTIVE: This study aimed to examine the level and predictors of knowledge of late effects risks from childhood cancer treatment in adolescent and young adult (AYA) survivors. METHODS: Seventy-three AYAs, aged 14-21, completed measures of knowledge of late effect risks, executive functioning, and responsibility for health self-management. Sixty-seven parents of these AYA survivors (91.7%) also participated. RESULTS: Survivors demonstrated poor knowledge of their unique risks for treatment-related late effects, with a mean accurate knowledge score of 54.29% (SD = 24.19%). The number of late effects for which survivors were at risk was negatively correlated with risk knowledge (r = -.34, p < .01). Survivors' executive functioning was not related to risk knowledge. In regression analyses, survivor age positively predicted accurate knowledge of late effects risks, and the number of late effects risk was a negative predictor. In separate models, survivor self-report of AYA responsibility for health self-management did not predict knowledge (R2 = .39, F = 10.86, p < .01), but parent proxy-report was a significant positive predictor (R2 = .38, F = 9.62, p < .01). Parental involvement was not a significant predictor in either model. CONCLUSION: There are significant knowledge gaps among AYA survivors of childhood cancer, which appear to be related to younger AYA age and lower levels of AYA responsibility for health self-management. Additional intervention is critical to increase AYA knowledge of their risk for late effects in order to promote continued engagement in long-term follow-up care and surveillance across the lifespan.

Association Between Medicaid Coverage Continuity and Survival in Patients With Newly Diagnosed Pediatric and Adolescent Cancers.

PURPOSE: Many patients with cancer do not gain Medicaid coverage until a cancer diagnosis, which can reduce access to early cancer detection and timely treatment, potentially driving inferior survival. Little is known about whether continuous Medicaid coverage prediagnosis through postdiagnosis (v gaining Medicaid at/after diagnosis) provides survival benefits for pediatric/adolescent oncology patients. MATERIALS AND METHODS: We identified patients newly diagnosed with cancer at age 21 years or younger in a large pediatric health system between 2007 and 2016. Electronic medical records (EMRs) were linked to Medicaid administrative data to differentiate insurance continuity patterns during the 6 months preceding through the 6 months after cancer diagnosis (assessment window): continuous Medicaid, newly gained Medicaid (at or after diagnosis), and other Medicaid enrollment patterns. For patients not linked to Medicaid data, we used EMR-reported insurance types at diagnosis. We followed patients from 6 months postdiagnosis up to 5 years, death, or December 2020, whichever came first. Multivariable regressions estimated all-cause and cancer-specific survival, controlling for sociodemographic and cancer-related factors. RESULTS: Among 1,800 patients included in the analysis, 1,293 (71.8%) had some Medicaid enrollment during the assessment window; among them, 47.6% had continuous Medicaid and 36.3% had newly gained Medicaid. Patients not linked with Medicaid data had private (26.9%) or other/no insurance (1.2%) at diagnosis. Compared with patients with continuous Medicaid, those with newly gained Medicaid had higher risks of all-cause death (hazard ratio [HR], 1.41 [95% CI, 1.10 to 1.81]; P = .008) and cancer-specific death (HR, 1.46 [95% CI, 1.12 to 1.90]; P = .005). CONCLUSION: Continuous Medicaid coverage throughout cancer diagnosis is associated with survival benefits for pediatric/adolescent patients. This finding has critical implications as millions of American individuals have been losing coverage since the unwinding of the Medicaid Continuous Enrollment Provision.

Feasibility of Fitbit Use in Adolescent Survivors of Pediatric Cancer: Who Consistently Uses It and for How Long?

Purpose: Wearable activity trackers with real-time feedback and goal-setting features are being incorporated into programs to increase physical activity among childhood cancer survivors. This analysis describes the adoption and use of a Fitbit® Flex™ among adolescent-aged survivors of childhood cancer without incentives, reminders, or interventions to encourage use. Procedures: Cancer survivors aged 13-18 and ≥2 years from therapy received a Fitbit Flex with instructions to wear it daily. Researchers downloaded participants' daily total steps and active minutes for 1 year. Participants were classified as consistent (≥5 days/week for >4 weeks during the first 12 weeks) or inconsistent users, and comparisons between user types were made. Longitudinal use of the Fitbit and participants' 1-year acceptability evaluations are described. Results: Overall, 67.1% (47/70) of survivors enrolled, and Fitbit data were available for 36 participants. Initially, 30.6% (11/36) were consistent users. Consistent users had lower body mass index z-scores at enrollment (0.4 ± 0.7 vs. 1.2 ± 0.9; p = 0.01), but were otherwise comparable with inconsistent users. Over time survivors' use declined; at 12 months, only one participant was using his or her Fitbit. Survivors who completed a survey (n = 22) reported their Fitbit helped them self-monitor their exercise (72.7%, 16/22) and lead a more active lifestyle (63.6%, 14/22), but found it challenging to charge and not lose, forget about, or break the device. Conclusions: In the real-world setting, only a small subset of adolescent-aged survivors will initially consistently use a Fitbit and their interest diminishes over time. To maximize engagement, interventions incorporating wearable activity trackers likely need to include additional behavior change strategies.

Implementation of Electronic Psychosocial Screening Among Caregivers in Pediatric Oncology.

PURPOSE: This study aimed to evaluate the reach and implementation of an electronic psychosocial screening program among caregivers of pediatric oncology patients, as well as characterize caregiver distress. METHODS: Participants (N = 2,013) included caregivers of patients age 0-17.99 years presenting across 9,280 outpatient oncology visits (median = 2; range = 1-52) from September 2018 to June 2019. At check-ins, caregivers electronically completed the pediatric distress thermometer via a patient-facing electronic health record (EHR) application. Caregiver distress ratings ≥ 8 triggered electronic alerts to medical teams to refer for social work support at point of care. Patient clinical and demographic differences in reach and fidelity were evaluated using univariate chi-square and t-tests. Caregivers reporting high distress were compared with caregivers without reports of high distress using univariate and multivariable logistic regression. RESULTS: The e-screening program was able to reach a caregiver for nearly all children seen during the study period, with 95.5% (1,923/2,013) of patients having a caregiver-completed pediatric distress thermometer. On screeners where caregivers reported high distress, medical teams made appropriate referrals to social work 95.5% (471/493) of the time. Overall, 16.9% (325/1,923) of caregivers ever indicated high distress (score ≥ 8), with caregivers of newly diagnosed (odds ratio = 3.16; 95% CI, 2.12 to 4.71) and on-therapy (odds ratio = 2.81; 95% CI, 2.11 to 3.76) patients being more likely to report high distress, compared with those who were off-treatment for the entire study. CONCLUSION: Leveraging EHR technology to provide evidence-based psychosocial screening can aid in successfully reaching a significant proportion of caregivers of pediatric oncology patients to identify and respond to ongoing psychosocial distress.

Evaluation of the Modified Reproductive Concerns Scale Among Emerging Adult Cancer Survivors.

Purpose: The reproductive concerns of emerging adult survivors of childhood cancer are not well described, and valid measurement tools tailored to this population are lacking. The purpose of this analysis was to evaluate a modified version of the Reproductive Concerns Scale (mRCS) among male and female survivors of childhood cancer. Methods: This is a secondary analysis of cross-sectional survey data collected from patients enrolled on an infertility-educational intervention study. Participants completed the mRCS at baseline. Cancer treatment data were abstracted from participant medical records. Principal component analyses were conducted to evaluate the factor structure of the mRCS for males, females, and the entire sample. Internal consistency was evaluated using Cronbach's alpha. Open-ended responses were analyzed and used to assess the validity of relevant quantitative items on the mRCS. Results: The sample consisted of N = 98 participants who were an average of 19.1 (±1.1) years of age, 45.9% were male, and 61.2% were non-Hispanic white. Factor analyses revealed three domains: Fertility Concerns (Cronbach's alpha = 0.77), Health Concerns (α = 0.74), and Information Seeking (α = 0.57). Sex-specific factor analyses identified differences in scale items for males. The open-ended responses aligned well with participant scores on the Fertility Concerns subscale. Conclusion: The mRCS consists of three subscales relevant to emerging adult survivors of childhood cancer. Further analysis by sex suggests that separate scales for males and females are warranted. Future research is warranted to determine the clinical utility of using the mRCS as a screening tool to identify and address reproductive concerns among emerging adult survivors.

Educational Intervention to Address Infertility-Related Knowledge Gaps Among Adolescent and Young Adult Survivors of Childhood Cancer.

Purpose: This study evaluates the impact of a personalized educational session on survivors' knowledge of risk for infertility and describes preferences for reproductive health care. Methods: This was a two-phase prospective study of an individualized education session for adolescent and young adult (AYA) survivors aged 18-21 years. Sessions used sex-specific visual aids (phase I) or a personalized handout (phase II). Surveys assessing knowledge of overall risk for infertility (yes/no), level of risk (none, low, moderate, or high), relative impact of treatment on the window of fertility (same/less than peers), and the need to use protection to prevent pregnancy (yes/no) were completed at baseline and 1-month follow-up. Changes in knowledge were assessed using McNemar's test. Preferences for fertility education and fertility status assessment were ascertained. Results: In phase I (n = 44), the educational intervention improved knowledge on the impact on the fertility window (from 69.7% correct responses to 90.9%; p = 0.03). In phase II (n = 54), the addition of a personalized, take-home visual aid significantly improved knowledge across all four concepts: knowledge of risk (68.4%-93.1%; p = 0.03), risk level (39.5%-86.8%; p < 0.001), impact on the fertility window (55.3%-86.8%; p = 0.003), and protection for pregnancy prevention (62.2%-81.1%; p = 0.03). Nearly all males (97%) and 66% of females preferred private sessions. The majority of survivors (73%) would like to undergo fertility status testing in the next 5 years. Conclusion: In this sample of AYA cancer survivors, individualized education sessions with personalized visual aids and assessment of survivors' understanding of information significantly improved knowledge of key reproductive health concepts.

Scalability of cancer SurvivorLink™: A cluster randomized trial among pediatric cancer clinics.

BACKGROUND: Children diagnosed with cancer are living longer and the survivor population is growing. However, most survivors develop late effects of radiation and chemotherapy shortly to years after completion of therapy, and the receipt of follow-up visits that are recommended by the Children's Oncology Group (COG) is suboptimal nationally. AIMS: The aims of this study are to: 1) evaluate the impact of a patient-controlled electronic personal health record (ePHR) and system (SurvivorLink) on care visit attendance, risk-based surveillance, and other secondary outcomes (i.e., patient activation, quality of life (QOL)); 2) measure the use, acceptability, and perceived usefulness of, and satisfaction with SurvivorLink; and 3) assess facilitators and barriers to implementation. METHODS: This hybrid effectiveness-implementation, clustered randomized control trial (RCT) evaluates the effect of SurvivorLink among pediatric cancer survivors and their parents on receipt of follow-up cancer care. We will recruit 20 pediatric survivor clinics with half receiving the intervention and half acting as a waitlist control. Parents of survivors and survivors will complete baseline, 3 and 12 month surveys that assess SurvivorLink use, patient self-efficacy, and intentions to return for follow-up. We will use mixed methods and multi-informant assessment to assess implementation outcomes (i.e., acceptability, feasibility, appropriateness). DISCUSSION: New approaches are needed to facilitate the receipt of long-term follow-up care among pediatric cancer survivors. This study will assess whether SurvivorLink is effective in increasing receipt of follow-up cancer care. Moreover, it will explore the influences of context and other moderators of clinical practice change in pediatric cancer survivorship.

Early Detection of Ovarian Dysfunction by Anti-Mullerian Hormone in Adolescent and Young Adult-Aged Survivors of Childhood Cancer.

PURPOSE: Current guidelines recommend screening at-risk childhood cancer survivors for ovarian dysfunction using follicle-stimulating hormone (FSH). However, FSH identifies diminished ovarian reserve (DOR), a component of ovarian dysfunction, in the later stages when fertility preservation is less likely to succeed. This analysis evaluates the utility of anti-Mullerian hormone (AMH) for the assessment of DOR in adolescent and young adult (AYA)-aged survivors of childhood cancer. METHODS: A retrospective chart review of 13- to 21-year-old female survivors who received gonadotoxic therapy and were ≥2 years off therapy was performed. Gonadotoxic treatments were categorized as low, moderate, or high risk for future infertility. Patients with AMH below the assay's age-specific normal range were identified and stratified by FSH values (normal ≤12 mIU/mL). Prevalence of low AMH and AMH-FSH subgroups was calculated and risk factors were evaluated using logistic regression. RESULTS: AMH was measured in 190 survivors who received gonadotoxic treatment; of them, 35.3% had low AMH. Among survivors who received <30 Gy cranial radiation and were not on hormone therapy (n = 141), 18.4% had normal FSH with low AMH. Stratified by future infertility risk, 10.6% of low-risk, 38.1% of moderate-risk, and 25.7% of high-risk survivors had normal FSH with low AMH (p < 0.01). Within the low-risk group, normal FSH with low AMH was significantly associated with older age at diagnosis (p = 0.02). CONCLUSION: Nearly 20% of AYA-aged at-risk survivors had low AMH and normal FSH. DOR in these patients would have been missed in standard recommended surveillance practices.