Assisted reproductive technology use and outcomes in childhood cancer survivors.

BACKGROUND: Treatment exposures for childhood cancer reduce ovarian reserve. However, the success of assisted reproductive technology (ART) among female survivors is not well established. METHODS: Five-year survivors of childhood cancer in the Childhood Cancer Survivor Study were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, which captures national ART outcomes. The authors assessed the live birth rate, the relative risk (RR) with 95% confidence intervals (95% CIs), and associations with treatment exposure using generalized estimating equations to account for multiple ovarian stimulations per individual. Siblings from a random sample of survivors were recruited to serve as a comparison group. RESULTS: Among 9885 female survivors, 137 (1.4%; median age at diagnosis, 10 years [range, 0-20 years]; median years of follow-up after age 18 years, 11 years [range, 2-11 years]) underwent 224 ovarian stimulations using autologous or donor eggs and/or gestational carriers (157 autologous ovarian stimulation cycles, 67 donor ovarian stimulation cycles). In siblings, 33 (1.4%) underwent 51 autologous or donor ovarian stimulations. Of those who used embryos from autologous eggs without using gestational carriers, 97 survivors underwent 155 stimulations, resulting in 49 live births, for a 31.6% chance of live birth per ovarian stimulation (vs. 38.3% for siblings; p = .39) and a 43.9% chance of live birth per transfer (vs. 50.0%; p = .33). Prior treatment with cranial radiation therapy (RR, 0.44; 95% CI, 0.20-0.97) and pelvic radiation therapy (RR, 0.33; 95% CI, 0.15-0.73) resulted in a reduced chance of live birth compared with siblings. The likelihood of live birth after ART treatment in survivors was not affected by alkylator exposure (cyclophosphamide-equivalent dose, ≥8000 mg/m2 vs. none; RR, 1.04; 95% CI, 0.52-2.05). CONCLUSIONS: Childhood cancer survivors are as likely to undergo treatment using ART as sibling controls. The success of ART treatment was not reduced after alkylator exposure. The results from the current study provide needed guidance on the use of ART in this population.

Factors influencing parents' choice of palliative treatment goals for children with relapsed or refractory neuroblastoma: A multi-site longitudinal survey study.

BACKGROUND: Many parents of children with advanced cancer report curative goals and continue intensive therapies that can compound symptoms and suffering. Factors that influence parents to choose palliation as the primary treatment goal are not well understood. The objective of this study was to examine experiences impacting parents' report of palliative goals adjusted for time. The authors hypothesized that awareness of poor prognosis, recall of oncologists' prognostic disclosure, intensive treatments, and burdensome symptoms and suffering would influence palliative goal-setting. METHODS: The authors collected prospective, longitudinal surveys from parents of children with relapsed/refractory neuroblastoma at nine pediatric cancer centers across the United States, beginning at relapse and continuing every 3 months for 18 months or until death. Hypothesized covariates were examined for possible associations with parental report of palliative goals. Generalized linear mixed models were used to evaluate factors associated with parents' report of palliative goals at different time points. RESULTS: A total of 96 parents completed surveys. Parents were more likely to report a primary goal of palliation when they recalled communication about prognosis by their child's oncologist (odds ratio [OR], 52.48; p = .010). Treatment intensity and previous ineffective therapeutic regimens were not associated with parents' report of palliative goals adjusted for time. A parent who reported new suffering for their child was less likely to report palliative goals (OR, 0.13; p = .008). CONCLUSIONS: Parents of children with poor prognosis cancer may not report palliative goals spontaneously in the setting of treatment-related suffering. Prognostic communication, however, does influence palliative goal-setting. Evidence-based interventions are needed to encourage timely, person-centered prognostic disclosure in the setting of advanced pediatric cancer. PLAIN LANGUAGE SUMMARY: Many parents of children with poor-prognosis cancer continue to pursue curative treatments that may worsen symptoms and suffering. Little is known about which factors influence parents to choose palliative care as their child's main treatment goal. To explore this question, we asked parents of children with advanced neuroblastoma across the United States to complete multiple surveys over time. We found that the intensity of treatment, number of treatments, and suffering from treatment did not influence parents to choose palliative goals. However, when parents remembered their child's oncologist talking about prognosis, they were more likely to choose palliative goals of care.

A nursing perspective on inpatient sleep and circadian disruptions for pediatric stem cell transplant patients.

BACKGROUND: Children treated with stem cell transplant (SCT) are routinely hospitalized for long periods where they are exposed to significant sleep and circadian disruptions. As nurses play a primary role in symptom management during SCT, we sought to understand their perspective on patient sleep and circadian disruptions, perceived barriers to a good sleep and circadian environment, and suggestions for improvement. PROCEDURE: Four focus groups were conducted with pediatric SCT nurses (N = 25 participants). A semistructured focus group guide was administered, with the discussions recorded and transcribed. A multistage thematic analysis combining prefigured and emergent dimensions was conducted. Our analysis focused on drawing comparisons within and across focus groups to understand the unique work experiences that participants had related to the patient's sleep and circadian environment. RESULTS: Three key themes emerged. First, nurses expressed a high awareness of how disruptive the hospital environment is for patients. Second, nurses described their extensive efforts to try to minimize the impact of these disruptions. Finally, they provided clear recommendations for how to improve upon these concerns, along with barriers that they perceive could impede implementation. CONCLUSIONS: Front-line caregivers on a pediatric SCT unit describe key contributors to sleep/circadian disturbances for patients. Within the constraints of the considerable medical needs of this patient population and the physical room/hospital environment, nurses strive to minimize these disruptions to the best of their ability. It is crucial that hospitals assess and remediate these disturbances for these children that have important implications for overall health.

Cumulative burden of late, major surgical intervention in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS) cohort.

BACKGROUND: Multimodal cancer therapy places childhood cancer survivors at increased risk for chronic health conditions, subsequent malignancies, and premature mortality as they age. We aimed to estimate the cumulative burden of late (>5 years from cancer diagnosis), major surgical interventions among childhood cancer survivors, compared with their siblings, and to examine associations between specific childhood cancer treatments and the burden of late surgical interventions. METHODS: We analysed data from the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study with longitudinal prospective follow-up of 5-year survivors of childhood cancer (diagnosed before age 21 years) treated at 31 institutions in the USA, with a comparison group of nearest-age siblings of survivors selected by simple random sampling. The primary outcome was any self-reported late, major surgical intervention (defined as any anaesthesia-requiring operation) occurring 5 years or more after the primary cancer diagnosis. The cumulative burden was assessed with mean cumulative counts (MCC) of late, major surgical interventions. Piecewise exponential regression models with calculation of adjusted rate ratios (RRs) evaluated associations between treatment exposures and late, major surgical interventions. FINDINGS: Between Jan 1, 1970, and Dec 31, 1999, 25 656 survivors were diagnosed (13 721 male, 11 935 female; median follow-up 21·8 years [IQR 16·5-28·4]; median age at diagnosis 6·1 years [3·0-12·4]); 5045 nearest-age siblings were also included as a comparison group. Survivors underwent 28 202 late, major surgical interventions and siblings underwent 4110 late, major surgical interventions. The 35-year MCC of a late, major surgical intervention was 206·7 per 100 survivors (95% CI 202·7-210·8) and 128·9 per 100 siblings (123·0-134·7). The likelihood of a late, major surgical intervention was higher in survivors versus siblings (adjusted RR 1·8, 95% CI 1·7-1·9) and in female versus male survivors (1·4; 1·4-1·5). Survivors diagnosed in the 1990s (adjusted RR 1·4, 95% CI 1·3-1·5) had an increased likelihood of late surgery compared with those diagnosed in the 1970s. Survivors received late interventions more frequently than siblings in most anatomical regions or organ systems, including CNS (adjusted RR 16·9, 95% CI 9·4-30·4), endocrine (6·7, 5·2-8·7), cardiovascular (6·6, 5·2-8·3), respiratory (5·3, 3·4-8·2), spine (2·4, 1·8-3·2), breast (2·1, 1·7-2·6), renal or urinary (2·0, 1·5-2·6), musculoskeletal (1·5, 1·4-1·7), gastrointestinal (1·4, 1·3-1·6), and head and neck (1·2, 1·1-1·4) interventions. Survivors of Hodgkin lymphoma (35-year MCC 333·3 [95% CI 320·1-346·6] per 100 survivors), Ewing sarcoma (322·9 [294·5-351·3] per 100 survivors), and osteosarcoma (269·6 [250·1-289·2] per 100 survivors) had the highest cumulative burdens of late, major surgical interventions. Locoregional surgery or radiotherapy cancer treatment were associated with undergoing late surgical intervention in the same body region or organ system. INTERPRETATION: Childhood cancer survivors have a significant burden of late, major surgical interventions, a late effect that has previously been poorly quantified. Survivors would benefit from regular health-care evaluations aiming to anticipate impending surgical issues and to intervene early in the disease course when feasible. FUNDING: US National Institutes of Health, US National Cancer Institute, American Lebanese Syrian Associated Charities, and St Jude Children's Research Hospital.

Neurocognitive outcomes in adult survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Despite survival improvements, there is a paucity of data on neurocognitive outcomes in neuroblastoma survivors. This study addresses this literature gap. METHODS: Neurocognitive impairments in survivors were compared to sibling controls from the Childhood Cancer Survivor Study (CCSS) using the CCSS Neurocognitive Questionnaire. Impaired emotional regulation, organization, task efficiency, and memory defined as scores ≥90th percentile of sibling norms. Modified Poisson regression models evaluated associations with treatment exposures, era of diagnosis, and chronic conditions. Analyses were stratified by age at diagnosis (≤1 and >1 year) as proxy for lower versus higher risk disease. RESULTS: Survivors (N = 837; median [range] age, 25 [17-58] years, age diagnosed, 1 [0-21] years) were compared to sibling controls (N = 728; age, 32 [16-43] years). Survivors had higher risk of impaired task efficiency (≤1 year relative risk [RR], 1.48; 95% confidence interval [CI], 1.08-2.03; >1 year RR, 1.58; 95% CI, 1.22-2.06) and emotional regulation (≤1 year RR, 1.51; 95% CI, 1.07-2.12; >1 year RR, 1.44; 95% CI, 1.06-1.95). Impaired task efficiency associated with platinum exposure (≤1 year RR, 1.74; 95% CI, 1.01-2.97), hearing loss (≤1 year RR, 1.95; 95% CI, 1.26-3.00; >1 year RR, 1.56; 95% CI, 1.09-2.24), cardiovascular (≤1 year RR, 1.83; 95% CI, 1.15-2.89; >1 year RR, 1.74; 95% CI, 1.12-2.69), neurologic (≤1 year RR, 2.00; 95% CI, 1.32-3.03; >1 year RR, 2.29; 95% CI, 1.64-3.21), and respiratory (>1 year RR, 2.35; 95% CI, 1.60-3.45) conditions. Survivors ≤1 year; female sex (RR, 1.54; 95% CI, 1.02-2.33), cardiovascular (RR, 1.71; 95% CI, 1.08-2.70) and respiratory (RR, 1.99; 95% CI, 1.14-3.49) conditions associated impaired emotional regulation. Survivors were less likely to be employed full-time (p < .0001), graduate college (p = .035), and live independently (p < .0001). CONCLUSIONS: Neuroblastoma survivors report neurocognitive impairment impacting adult milestones. Identified health conditions and treatment exposures can be targeted to improve outcomes. PLAIN LANGUAGE SUMMARY: Survival rates continue to improve in patients with neuroblastoma. There is a lack of information regarding neurocognitive outcomes in neuroblastoma survivors; most studies examined survivors of leukemia or brain tumors. In this study, 837 adult survivors of childhood neuroblastoma were compared to siblings from the Childhood Cancer Survivorship Study. Survivors had a 50% higher risk of impairment with attention/processing speed (task efficiency) and emotional reactivity/frustration tolerance (emotional regulation). Survivors were less likely to reach adult milestones such as living independently. Survivors with chronic health conditions are at a higher risk of impairment. Early identification and aggressive management of chronic conditions may help mitigate the level of impairment.

Impact of diagnostic and end-of-induction Curie scores with tandem high-dose chemotherapy and autologous transplants for metastatic high-risk neuroblastoma: A report from the Children's Oncology Group.

BACKGROUND: Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end-of-induction (EOI) Curie scores (CS) was previously described in patients undergoing a single course of high-dose chemotherapy (HDC) and autologous hematopoietic cell transplant (AHCT) as consolidation therapy. OBJECTIVE: We now examine the prognostic significance of CS in patients randomized to tandem HDC and AHCT on the Children's Oncology Group (COG) trial ANBL0532. STUDY DESIGN: A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 was performed. Evaluable patients had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received either single or tandem HDC (n = 80). Optimal CS cut points maximized the outcome difference (≤CS vs. >CS cut-off) according to the Youden index. RESULTS: For recipients of tandem HDC, the optimal cut point at diagnosis was CS = 12, with superior event-free survival (EFS) from study enrollment for patients with CS ≤ 12 (3-year EFS 74.2% ± 7.9%) versus CS > 12 (59.2% ± 7.1%) (p = .002). At EOI, the optimal cut point was CS = 0, with superior EOI EFS for patients with CS = 0 (72.9% ± 6.4%) versus CS > 0 (46.5% ± 9.1%) (p = .002). CONCLUSION: In the setting of tandem transplantation for children with high-risk neuroblastoma, CS at diagnosis and EOI may identify a more favorable patient group. Patients treated with tandem HDC who exhibited a CS ≤ 12 at diagnosis or CS = 0 at EOI had superior EFS compared to those with CS above these cut points.

Universal newborn genetic screening for pediatric cancer predisposition syndromes: model-based insights.

PURPOSE: Genetic testing for pediatric cancer predisposition syndromes (CPS) could augment newborn screening programs, but with uncertain benefits and costs. METHODS: We developed a simulation model to evaluate universal screening for a CPS panel. Cohorts of US newborns were simulated under universal screening versus usual care. Using data from clinical studies, ClinVar, and gnomAD, the presence of pathogenic/likely pathogenic (P/LP) variants in RET, RB1, TP53, DICER1, SUFU, PTCH1, SMARCB1, WT1, APC, ALK, and PHOX2B were assigned at birth. Newborns with identified variants underwent guideline surveillance. Survival benefit was modeled via reductions in advanced disease, cancer deaths, and treatment-related late mortality, assuming 100% adherence. RESULTS: Among 3.7 million newborns, under usual care, 1,803 developed a CPS malignancy before age 20. With universal screening, 13.3% were identified at birth as at-risk due to P/LP variant detection and underwent surveillance, resulting in a 53.5% decrease in cancer deaths in P/LP heterozygotes and a 7.8% decrease among the entire cohort before age 20. Given a test cost of $55, universal screening cost $244,860 per life-year gained; with a $20 test, the cost fell to $99,430 per life-year gained. CONCLUSION: Population-based genetic testing of newborns may reduce mortality associated with pediatric cancers and could be cost-effective as sequencing costs decline.

Socioeconomic disparities in survival after high-risk neuroblastoma treatment with modern therapy.

BACKGROUND: Modern therapeutic advances in high-risk neuroblastoma have improved overall survival (OS), but it is unclear whether these survival gains have been equitable. This study examined the relationship between socioeconomic status (SES) and overall survival (OS) in children with high-risk neuroblastoma and whether SES-associated disparities have changed over time. PROCEDURE: In this population-based cohort study, children <18 years diagnosed with high-risk neuroblastoma (diagnosis at age ≥12 months with metastatic disease) from 1991 to 2015 were identified through the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Associations of county-level SES variables and OS were tested with univariate Cox proportional hazards regression. For a subcohort diagnosed after 2007, insurance status was examined as an individual-level SES variable. Multivariable regression analyses with treatment era and interaction terms were performed when SES variables reached near-significance (p ≤ .1) in univariate and bivariate modeling with treatment era. RESULTS: Among 1217 children, 2-year OS improved from 53.0 ± 3.4% in 1991-1998 to 76.9 ± 2.9% in 2011-2015 (p < .001). In univariate analyses, children in high-poverty counties (hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.17-2.60, p = .007), and those with Medicaid (HR = 1.40, 95% CI = 1.05-1.86, p = .02) experienced an increased hazard of death. No interactions between treatment era and SES variables were statistically significant in multivariable analyses, indicating that differences in the OS between SES groups did not change over time. CONCLUSIONS: Survival disparities among children with high-risk neuroblastoma have not widened over time, suggesting equitable access to and benefit from therapeutic advances. However, children of low SES experience persistently inferior survival. Interventions to narrow this disparity are paramount.

Clinical Benefits, Harms, and Cost-Effectiveness of Breast Cancer Screening for Survivors of Childhood Cancer Treated With Chest Radiation : A Comparative Modeling Study.

BACKGROUND: Surveillance with annual mammography and breast magnetic resonance imaging (MRI) is recommended for female survivors of childhood cancer treated with chest radiation, yet benefits, harms, and costs are uncertain. OBJECTIVE: To compare the benefits, harms, and cost-effectiveness of breast cancer screening strategies in childhood cancer survivors. DESIGN: Collaborative simulation modeling using 2 Cancer Intervention and Surveillance Modeling Network breast cancer models. DATA SOURCES: Childhood Cancer Survivor Study and published data. TARGET POPULATION: Women aged 20 years with a history of chest radiotherapy. TIME HORIZON: Lifetime. PERSPECTIVE: Payer. INTERVENTION: Annual MRI with or without mammography, starting at age 25, 30, or 35 years. OUTCOME MEASURES: Breast cancer deaths averted, false-positive screening results, benign biopsy results, and incremental cost-effectiveness ratios (ICERs). RESULTS OF BASE-CASE ANALYSIS: Lifetime breast cancer mortality risk without screening was 10% to 11% across models. Compared with no screening, starting at age 25 years, annual mammography with MRI averted the most deaths (56% to 71%) and annual MRI (without mammography) averted 56% to 62%. Both strategies had the most screening tests, false-positive screening results, and benign biopsy results. For an ICER threshold of less than $100 000 per quality-adjusted life-year gained, screening beginning at age 30 years was preferred. RESULTS OF SENSITIVITY ANALYSIS: Assuming lower screening performance, the benefit of adding mammography to MRI increased in both models, although the conclusions about preferred starting age remained unchanged. LIMITATION: Elevated breast cancer risk was based on survivors diagnosed with childhood cancer between 1970 and 1986. CONCLUSION: Early initiation (at ages 25 to 30 years) of annual breast cancer screening with MRI, with or without mammography, might reduce breast cancer mortality by half or more in survivors of childhood cancer. PRIMARY FUNDING SOURCE: American Cancer Society and National Institutes of Health.

Linking population-based registries to identify familial cancer risk in childhood cancer.

BACKGROUND: Linked population-based registries provide a unique source for identification of new family cancer syndromes and for elucidating risk of early-onset cancer in close relatives of cancer patients. METHODS: Using the Finnish Cancer Registry, we identified 9078 probands who had been diagnosed with cancer at <21 years of age between 1970 and 2012. Siblings, offspring, parents, nephews, and nieces of probands were identified from the Population Registry. Childhood and young adult (ChYA) cancer diagnoses (age 0-39 years) in relatives were identified by linking to the Finnish Cancer Registry. The relative risk of ChYA cancer in family members of probands was estimated using standardized incidence ratios (SIRs). RESULTS: Among 58,010 family members of the 9078 probands, 363 ChYA cancers were diagnosed, 324 of which were expected (SIR, 1.12; 95% CI, 1.01-1.24). The risk of ChYA cancer was elevated both in offspring (SIR, 2.25; 95% CI, 1.51-3.24) and in siblings (SIR, 1.17; 95% CI, 1.01-1.36). Offspring of probands with retinoblastoma were at highest risk (SIR, 75.85; 95% CI, 32.75-149.45); risks were also elevated for siblings of probands with lymphoma (SIR, 1.62; 95% CI, 1.14-2.25). Known cancer predisposition syndromes were observed in 29 (66%) of 44 sibling pairs with cancers diagnosed at <21 years of age and in 20% of the 135 families with a childhood cancer proband whose sibling was diagnosed with a young adult malignancy. CONCLUSION: Linked population-based registry data indicate a modestly increased risk of ChYA in relatives of children with cancer. Some of the observed cancer clusters in the cohort suggest novel patterns and familial cancer syndromes.

Unrealistic parental expectations for cure in poor-prognosis childhood cancer.

BACKGROUND: Many parents of children with advanced cancer pursue curative goals when cure is no longer possible. To the authors' knowledge, no pediatric studies to date have prospectively evaluated prognosis communication or influences on decision making in poor-prognosis childhood cancer. METHODS: The authors conducted a prospective cohort study at 9 pediatric cancer centers that enrolled 95 parents of children with recurrent or refractory, high-risk neuroblastoma (63% of those who were approached), a condition for which cure rarely is achieved. Parents were surveyed regarding the child's likelihood of cure; their primary goal of care; the child's symptoms, suffering, and quality of life; and regret concerning the last treatment decision. Medical records identified care and treatment decisions. RESULTS: Only 26% of parents recognized that the chance of cure was <25%. When asked to choose a single most important goal of care, approximately 72% chose cure, 10% chose longer life, and 18% chose quality of life. Parents were more likely to prioritize quality of life when they recognized the child's poor prognosis (P = .002). Approximately 41% of parents expressed regret about the most recent treatment decision. Parents were more likely to experience regret if the child had received higher intensity medical care (odds ratio [OR], 3.14; 95% CI, 1.31-7.51), experienced suffering with limited benefit from the most recent treatment (OR, 4.78; 95% CI, 1.16-19.72), or experienced suffering from symptoms (OR, 2.91; 95% CI, 1.18-7.16). CONCLUSIONS: Parents of children with poor-prognosis cancer frequently make decisions based on unrealistic expectations. New strategies for effective prognosis communication are needed.

Solid organ transplantation after treatment for childhood cancer: a retrospective cohort analysis from the Childhood Cancer Survivor Study.

BACKGROUND: Serious chronic medical conditions occur in childhood cancer survivors. We aimed to investigate incidence of and risk factors for end-organ damage resulting in registration on a waiting list for or receiving a solid organ transplantation and 5-year survival following these procedures. METHODS: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of individuals who survived at least 5 years after childhood cancer diagnosed at younger than 21 years of age, between Jan 1, 1970, and Dec 31, 1986, at one of 25 institutions in the USA. We linked data from CCSS participants treated in the USA diagnosed between Jan 1, 1970, and Dec 31, 1986 (without solid organ transplantation before cohort entry) to the Organ Procurement and Transplantation Network-a database of all US organ transplants. Eligible participants had been diagnosed with leukaemia, lymphoma, malignant CNS tumours, neuroblastoma, Wilms' tumours, and bone and soft tissue sarcomas. The two primary endpoints for each type of organ transplant were date of first registration of a transplant candidate on the waiting list for an organ and the date of the first transplant received. We also calculated the cumulative incidence of being placed on a waiting list or receiving a solid organ transplantation, hazard ratios (HRs) for identified risk factors, and 5-year survival following transplantation. FINDINGS: Of 13 318 eligible survivors, 100 had 103 solid organ transplantations (50 kidney, 37 heart, nine liver, seven lung) and 67 were registered on a waiting list without receiving a transplant (21 kidney, 25 heart, 15 liver, six lung). At 35 years after cancer diagnosis, the cumulative incidence of transplantation or being on a waiting list was 0·54% (95% CI 0·40-0·67) for kidney transplantation, 0·49% (0·36-0·62) for heart, 0·19% (0·10-0·27) for liver, and 0·10% (0·04-0·16) for lung. Risk factors for kidney transplantation were unilateral nephrectomy (HR 4·2, 95% CI 2·3-7·7), ifosfamide (24·9, 7·4-83·5), total body irradiation (6·9, 2·3-21·1), and mean kidney radiation of greater than 15 Gy (>15-20 Gy, 3·6 [1·5-8·5]; >20 Gy 4·6 [1·1-19·6]); for heart transplantation, anthracycline and mean heart radiation of greater than 20 Gy (dose-dependent, both p<0·0001); for liver transplantation, dactinomycin (3·8, 1·3-11·3) and methotrexate (3·3, 1·0-10·2); for lung transplantation, carmustine (12·3, 3·1-48·9) and mean lung radiation of greater than 10 Gy (15·6, 2·6-92·7). 5-year overall survival after solid organ transplantation was 93·5% (95% CI 81·0-97·9) for kidney transplantation, 80·6% (63·6-90·3) for heart, 27·8% (4·4-59·1) for liver, and 34·3% (4·8-68·6) for lung. INTERPRETATION: Solid organ transplantation is uncommon in ageing childhood cancer survivors. Organ-specific exposures were associated with increased solid organ transplantation incidence. Survival outcomes showed that solid organ transplantation should be considered for 5-year childhood cancer survivors with severe end-organ failure. FUNDING: US National Institute of Health, American Lebanese Syrian Associated Charities, US Health Resources and Services Administration.

Late-onset anorectal disease and psychosocial impact in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

BACKGROUND: The prevalence and associated psychosocial morbidity of late-onset anorectal disease after surgery and radiotherapy for the treatment of childhood cancer are not known. METHODS: A total of 25,530 survivors diagnosed between 1970 and 1999 (median age at cancer diagnosis, 6.1 years; age at survey, 30.2 years) and 5036 siblings were evaluated for late-onset anorectal disease, which was defined as a self-reported fistula-in-ano, self-reported anorectal stricture, or pathology- or medical record-confirmed anorectal subsequent malignant neoplasm (SMN) 5 or more years after the primary cancer diagnosis. Piecewise exponential models compared the survivors and siblings and examined associations between cancer treatments and late-onset anorectal disease. Multiple logistic regression with generalized estimating equations was used to evaluate associations between late-onset anorectal disease and emotional distress, as defined by the Brief Symptom Inventory 18 (BSI-18), and health-related quality of life, as defined by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). RESULTS: By 45 years after the diagnosis, 394 survivors (fistula, n = 291; stricture, n = 116; anorectal SMN, n = 26) and 84 siblings (fistula, n = 73; stricture, n = 23; anorectal neoplasm, n = 1) had developed late-onset anorectal disease (adjusted rate ratio [RR] for survivors vs siblings, 1.2; 95% confidence interval [CI], 1.0-1.5). Among survivors, pelvic radiotherapy with ≥30 Gy within 5 years of the cancer diagnosis was associated with late-onset anorectal disease (adjusted RR for 30-49.9 Gy vs none, 1.6; 95% CI, 1.1-2.3; adjusted RR for ≥50 Gy vs none, 5.4; 95% CI, 3.1-9.2). Late-onset anorectal disease was associated with psychosocial impairment in all BSI-18 and SF-36 domains. CONCLUSIONS: Late-onset anorectal disease was more common among childhood cancer survivors who received higher doses of pelvic radiotherapy and was associated with substantial psychosocial morbidity.

Risk of solid subsequent malignant neoplasms after childhood Hodgkin lymphoma-Identification of high-risk populations to guide surveillance: A report from the Late Effects Study Group.

BACKGROUND: Survivors of Hodgkin lymphoma (HL) in childhood have an increased risk of subsequent malignant neoplasms (SMNs). Herein, the authors extended the follow-up of a previously reported Late Effects Study Group cohort and identified patients at highest risk for SMNs to create evidence for risk-based screening recommendations. METHODS: The standardized incidence ratio was calculated using rates from the Surveillance, Epidemiology, and End Results program as a reference. The risk of SMN was estimated using proportional subdistribution hazards regression. The cohort included 1136 patients who were diagnosed with HL before age 17 years between 1955 and 1986. The median length of follow-up was 26.6 years. RESULTS: In 162 patients, a total of 196 solid SMNs (sSMNs) were identified. Compared with the general population, the cohort was found to be at a 14-fold increased risk of developing an sSMN (95% confidence interval, 12.0-fold to 16.3-fold). The cumulative incidence of any sSMN was 26.4% at 40 years after a diagnosis of HL. Risk factors for breast cancer among females were an HL diagnosis between ages 10 years and 16 years and receipt of chest radiotherapy. Males treated with chest radiotherapy at age <10 years were found to be at highest risk of developing lung cancer. Survivors of HL who were treated with abdominal/pelvic radiotherapy and high-dose alkylating agents were found to be at highest risk of developing colorectal cancer and females exposed to neck radiotherapy at age <10 years were at highest risk of thyroid cancer. By age 50 years, the cumulative incidence of breast, lung, colorectal, and thyroid cancer was 45.3%, 4.2%, 9.5%, and 17.3%, respectively, among those at highest risk. CONCLUSIONS: Survivors of childhood HL remain at an increased risk of developing sSMNs. In the current study, subgroups of survivors of HL at highest risk of specific sSMNs were identified, and evidence for screening provided.

Role of the extent of prophylactic regional lymph node radiotherapy on survival in high-risk neuroblastoma: A report from the COG A3973 study.

PURPOSE: Neuroblastoma is the most common extracranial solid pediatric malignancy, with poor outcomes in high-risk disease. Standard treatment approaches employ an increasing array of aggressive multimodal therapies, of which local control with surgery and radiotherapy remains a backbone; however, the benefit of broad regional nodal irradiation remains controversial. We analyzed centrally reviewed radiation therapy data from patients enrolled on COG A3973 to evaluate the impact of primary site irradiation and the extent of regional nodal coverage stratified by extent of surgical resection. METHODS: Three hundred thirty high-risk neuroblastoma patients with centrally reviewed radiotherapy plans were analyzed. Outcome was evaluated by the extent of nodal irradiation. For the 171 patients who also underwent surgery (centrally reviewed), outcome was likewise analyzed according to the extent of resection. Overall survival (OS), event-free survival (EFS), and cumulative incidence of local progression (CILP) were examined by Kaplan-Meier, log-rank test (EFS, OS), and Grey test (CILP). RESULTS: The five-year CILP, EFS, and OS for all 330 patients receiving radiotherapy on A3973 were 8.5% ± 1.5%, 47.2% ± 3.0%, and 59.7% ± 3.0%, respectively. There were no significant differences in outcomes based on the extent of lymph node irradiation regardless of the degree of surgical resection (< 90% or ≥90%). CONCLUSION: Although local control remains a significant component of treatment of high-risk neuroblastoma, our results suggest there is no benefit of extensive lymph node irradiation, irrespective of the extent of surgical resection preceding stem cell transplant.

Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients With High-Risk Neuroblastoma: A Randomized Clinical Trial.

Importance: Induction chemotherapy followed by high-dose therapy with autologous stem cell transplant and subsequent antidisialoganglioside antibody immunotherapy is standard of care for patients with high-risk neuroblastoma, but survival rate among these patients remains low. Objective: To determine if tandem autologous transplant improves event-free survival (EFS) compared with single transplant. Design, Setting, and Participants: Patients were enrolled in this randomized clinical trial from November 2007 to February 2012 at 142 Children's Oncology Group centers in the United States, Canada, Switzerland, Australia, and New Zealand. A total of 652 eligible patients aged 30 years or younger with protocol-defined high-risk neuroblastoma were enrolled and 355 were randomized. The final date of follow-up was June 29, 2017, and the data analyses cut-off date was June 30, 2017. Interventions: Patients were randomized to receive tandem transplant with thiotepa/cyclophosphamide followed by dose-reduced carboplatin/etoposide/melphalan (n = 176) or single transplant with carboplatin/etoposide/melphalan (n = 179). Main Outcomes and Measures: The primary outcome was EFS from randomization to the occurrence of the first event (relapse, progression, secondary malignancy, or death from any cause). The study was designed to test the 1-sided hypothesis of superiority of tandem transplant compared with single transplant. Results: Among the 652 eligible patients enrolled, 297 did not undergo randomization because they were nonrandomly assigned (n = 27), ineligible for randomization (n = 62), had no therapy (n = 1), or because of physician/parent preference (n = 207). Among 355 patients randomized (median diagnosis age, 36.1 months; 152 [42.8%] female), 297 patients (83.7%) completed the study and 21 (5.9%) were lost to follow-up after completing protocol therapy. Three-year EFS from the time of randomization was 61.6% (95% CI, 54.3%-68.9%) in the tandem transplant group and 48.4% (95% CI, 41.0%-55.7%) in the single transplant group (1-sided log-rank P=.006). The median (range) duration of follow-up after randomization for 181 patients without an event was 5.6 (0.6-8.9) years. The most common significant toxicities following tandem vs single transplant were mucosal (11.7% vs 15.4%) and infectious (17.9% vs 18.3%). Conclusions and Relevance: Among patients aged 30 years or younger with high-risk neuroblastoma, tandem transplant resulted in a significantly better EFS than single transplant. However, because of the low randomization rate, the findings may not be representative of all patients with high-risk neuroblastoma. Trial Registration: ClinicalTrials.gov Identifier: NCT00567567.

Long-term psychological and educational outcomes for survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Neuroblastoma survivors may be at elevated risk for psychological impairments because of their young age at diagnosis and neurotoxic treatment, but this is not well described. METHODS: A total of 859 ≥5-year survivors of neuroblastoma younger than 18 years (diagnosed in 1970-1999), who had a median age at diagnosis of 0.8 years (range: 0.0-7.3 years) and a median follow-up of 13.3 years (range: 8.0-17.9 years), were compared with 872 siblings of childhood cancer survivors who were younger than 18 years with the parent-reported Behavior Problem Index (BPI) for psychological functioning. Age- and sex-adjusted multivariate log-binomial models were used to identify factors associated with impairment in BPI domains (scores worse than the sibling 10th percentile). The impact of psychological impairment on educational outcomes was examined among survivors. RESULTS: Compared with siblings, neuroblastoma survivors had an increased prevalence of impairment in the domains of anxiety/depression (19% vs 14%; P = .003), headstrong behavior (19% vs 13%; P < .001), attention deficits (21% vs 13%; P < .001), peer conflict/social withdrawal (26% vs 17%; P < .001), and antisocial behavior (16% vs 12%; P = .01). Common treatment exposures (vincristine, cisplatin, and retinoic acid) were not associated with impairment. Having 2 or more chronic health conditions predicted impairment in 4 domains (P < .001). Specifically, pulmonary disease predicted impairment in all 5 domains (P ≤ .004). Endocrine disease (P ≤ .004) and peripheral neuropathy (P ≤ .02) each predicted impairment in 3 domains. Psychological impairment was associated with special education service usage and educational attainment less than college. CONCLUSIONS: Neuroblastoma survivors are at elevated risk for psychological impairment, which is associated with special education service usage and lower adult educational attainment. Those with chronic health conditions may represent a high-risk group for targeted screening and intervention. Cancer 2018. © 2018 American Cancer Society.

Perceptions of future health and cancer risk in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Survivors of childhood cancer are at significant risk for serious chronic health conditions and subsequent cancers because of their prior treatment exposures. However, little is known about survivors' perceptions of their future health risks. METHODS: This study examined self-reported levels of concern about future health and subsequent cancer in 15,620 adult survivors of childhood cancer (median age, 26 years; median time since diagnosis, 17 years) and 3991 siblings in the Childhood Cancer Survivor Study. The prevalence of concerns was compared between survivors and siblings, and the impact of participant characteristics and treatment exposures on concerns was examined with multivariable modified Poisson regression to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: A substantial proportion of survivors were not concerned about their future health (31%) or developing cancer (40%). The prevalence of concern in survivors was modestly higher (RR for future health, 1.12; 95% CI, 1.09-1.15) or similar (RR for subsequent cancer, 1.02; 95% CI, 0.99-1.05) in comparison with siblings. Survivors exposed to high doses of radiation (≥20 Gy) were more likely to report concern (RR for future health, 1.13; 95% CI, 1.09-1.16; RR for subsequent cancer, 1.14; 95% CI, 1.10-1.18), but 35% of these high-risk survivors were not concerned about developing cancer, and 24% were not concerned about their future health. CONCLUSIONS: A substantial subgroup of survivors were unconcerned about their future health and subsequent cancer risks, even after exposure to treatments associated with increased risk. These survivors may be less likely to engage in beneficial screening and risk-reduction activities. Cancer 2018. © 2018 American Cancer Society.

Screening with whole-body magnetic resonance imaging in pediatric subjects with Li-Fraumeni syndrome: A single institution pilot study.

BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the TP53 gene and a high risk of childhood-onset malignancies. Cancer surveillance is challenging in pediatric mutation carriers given the anatomic spectrum of malignancies and young age of onset. Whole-body magnetic resonance imaging (WB-MRI) may provide an acceptable method for early cancer detection. PROCEDURE: We conducted a prospective feasibility pilot study of pediatric subjects (age < 18 years) with LFS to determine return rates for annual WB-MRI scan. Secondary objectives included characterization of incident cancers (and how they were detected). RESULTS: Forty-five WB-MRI scans in 20 subjects were performed over 5 years; two patients enrolled without subsequently undergoing scans. Eighty-nine percent of participants scanned (95% confidence interval: 67-99%) returned for second examinations. Fifty-five percent of participants required general anesthesia, which was well tolerated in all cases. Six patients required dedicated follow-up imaging. One participant required biopsy of a detected brain lesion; pathology demonstrated reactive gliosis. Another participant, with prior choroid plexus carcinoma, had a new brain lesion detected on clinical follow-up MRI not seen on WB-MRI 6 months prior. All other participants remain well (median: 3 years, range: 0.08-4 years). CONCLUSIONS: WB-MRI in pediatric subjects is a well-tolerated approach to cancer surveillance despite the need for general anesthesia in some patients. A large multicenter trial would determine true test characteristics and efficacy of this approach for early cancer detection in children at high cancer risk.