Treatment-related cardiac death is the primary non-cancer cause of mortality in adult survivors of childhood malignancies. Early detection of cardiac dysfunction using modern echocardiographic techniques may identify a high risk subset of survivors for early intervention.
To determine the prevalence of cardiac dysfunction in adult survivors of childhood malignancies using state of the art echocardiographic evaluation of cardiac function including strain imaging
Echocardiographic assessment included three dimensional (3D) left ventricular ejection fraction (LVEF), global longitudinal and circumferential myocardial strain and diastolic function, graded per American Society of Echocardiography (ASE) guidelines on 1,820 adult (median age 31 [range 18-65] years) survivors of childhood cancer (median time from diagnosis 23 years [range10-48] years) exposed to either anthracycline chemotherapy (N=1,050), chest-directed radiotherapy (RT, N=306), or both therapies (N=464).
Only 5.8% of survivors had an abnormal 3D LVEF (<50%). However, 32.1% of survivors with a normal 3D LVEF had evidence for cardiac dysfunction by either global longitudinal strain (28.0%), ASE graded diastolic assessment (8.7%), or both. Abnormal global longitudinal strain was associated with chest-directed RT (1-19.9 Gy, Rate Ratio (RR) 1.38, 95% Confidence Interval (CI) 1.14-1.66; 20-29.9 Gy, RR 1.65, 95% CI 1.31-2.08; >30 Gy, RR 2.39, 95% CI 1.79-3.18) and anthracycline dose >300 mg/m2 (RR 1.72, 95% CI 1.31-2.26). Survivors with metabolic syndrome were twice as likely to have abnormal global longitudinal strain (Rate Ratio [RR] 1.94, 95% CI 1.66-2.28) as well as abnormal diastolic function (RR 1.68, 95% CI 1.39-2.03), but not abnormal 3D LVEF (RR 1.07, 95% CI 0.74-1.53).
Conclusions and Relevance
Abnormal global longitudinal strain and abnormal diastolic function are more prevalent than reduced 3D LVEF and are associated with treatment exposure. They may identify a subset of survivors at higher risk for poor clinical cardiac outcome who may benefit from early medical intervention.
Childhood Cancer; Survivor; Late effects; Cardiotoxicity; Screening
Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer.
We did semen analysis on 214 adult male survivors of childhood cancer (median age 7·7 years [range 0·01–20·3] at diagnosis, 29·0 years [18·4–56·1] at assessment, and a median of 21·0 years [10·5–41·6] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling.
Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration ≥15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m2 were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=–0·37, p<0·0001). Mean CED was 10 830 mg/m2 (SD 7274) in patients with azoospermia, 8480 mg/m2 (4264) in patients with oligospermia, and 6626 mg/m2 (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m2 CED for azoospermia (OR 1·22, 95% CI 1·11–1·34), and for oligospermia (1·14, 1·04–1·25), but age at diagnosis and age at assessment were not.
Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m2. Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services.
Treatments for childhood cancer can impair pulmonary function. We assessed the potential impact of cigarette smoking on pulmonary function in 433 adult childhood cancer survivors (CCS) who received pulmonary-toxic therapy, using single breath diffusion capacity for carbon monoxide corrected for hemoglobin (DLCOcorr), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and total lung capacity (TLC). FEV1/FVC median values among current (1.00; interquartile range (IQR): 0.94–1.04) and former smokers (0.98; IQR: 0.93–1.04) were lower than those who had never smoked (1.02; IQR: 0.96–1.06) (p = 0.003). Median FEV1/FVC values were lower among those who smoked ≥ 6 pack-years (0.99; IQR: 0.92–1.03) and those who smoked < 6 pack-years (1.00; IQR: 0.94–1.04), than among those who had never smoked (p=0.005). Our findings suggest that CCS have an increased risk for future obstructive and restrictive lung disease. Follow-up is needed to determine if smoking imparts more than additive risk. Smoking prevention and cessation need to be a priority in this population.
Addictive substances/nicotine; Epidemiology of survivorship; Long-term toxicities
Treatment cures over 90% of children with Wilms tumor (WT) who subsequently risk late morbidity and mortality. This study describes the 25-year outcomes of 5-year Wilms tumor survivors in the Childhood Cancer Survivor Study (CCSS).
The CCSS, a multi-institutional retrospective cohort study, assessed Wilms tumor survivors (n=1256), diagnosed 1970 – 1986, for chronic health conditions, health status, health care utilization, socioeconomic status, subsequent malignant neoplasms (SMNs), and mortality compared to the US population and a sibling cohort (n=4023).
The cumulative incidence of all and severe chronic health conditions was 65.4% and 24.2% at 25 years. Hazard Ratios [HR] were 2.0, 95% Confidence Interval [CI], 1.8-2.3 for grades 1 -4 and 4.7, 95% CI, 3.6-6.1 for grade 3-4, compared to sibling group. WT survivors reported more adverse general health status than the sibling group (Prevalence Ratio [PR] 1.7; 95% CI, 1.2–2.4), but mental health status, socioeconomic outcome, and health care utilization were similar. The cumulative incidence of SMN was 3.0% (95%CI, 1.9–4.0%) and of mortality was 6.1% (95%CI, 4.7-7.4%). Radiation exposure increased the likelihood of congestive heart failure (CHF) (no doxorubicin - HR 6.6; 95%CI, 1.6-28.3; doxorubicin ≤ 250 mg/m2 - HR 13.0; 95%CI, 1.9-89.7; doxorubicin > 250 mg/m2 - HR 18.3; 95%CI, 3.8-88.2), SMN (Standardized Incidence Ratio [SIR] 9.0; 95%CI, 3.9-17.7 with and 4.9; 95%CI, 1.8-10.6 without doxorubicin) and death.
Long-term survivors of WT treated from 1970 to 1986 are at increased risk of treatment related morbidity and mortality 25 years from diagnosis.
Wilms Tumor; late effects; survivorship
Many male survivors of childhood cancer are at risk for azoospermia. Although both the levels of follicle-stimulating hormone (FSH) and inhibin B are correlated with sperm concentration, their ability to predict azoospermia in survivors of childhood cancer remains uncertain.
Patients and Methods
Semen analysis was performed and serum levels of FSH and inhibin B were measured in 275 adult male survivors of childhood cancer who had received gonadotoxic therapy. Receiver operating characteristic (ROC) analysis was performed to determine the optimal inhibin B and FSH values for identifying patients with azoospermia. The patient sample was divided into a learning set and a validation set. Sensitivity, specificity, and positive and negative predictive value were calculated.
Inhibin B was dichotomized as ≤ 31 ng/L or more than 31 ng/L and FSH was dichotomized as ≤ 11.5 mIU/mL or more than 11.5 mIU/mL based on results of the ROC analysis. Using these values, the specificity of the serum level of inhibin B for identifying azoospermic survivors was 45.0%, and the positive predictive value was 52.1%. The specificity for FSH was 74.1%, and the positive predictive value was 65.1%.
Neither serum inhibin B nor FSH is a suitable surrogate for determination of sperm concentration in a semen sample. Young men and their physicians should be aware of the limitations of these measures for assessment of fertility potential.
Childhood cancer survivors (CCS) treated with anthracyclines are at risk for cardiomyopathy. This case series evaluated the response of anthracycline exposed CCS with subclinical cardiomyopathy to aerobic and strength training. Body composition, strength and cardiopulmonary fitness were evaluated before and after the 12-week intervention. All equipment and materials were provided to five 10+ year CCS (3 males, mean age 38.0±3.3 years) for a guideline-based home exercise program. All five completed the study with no adverse events. Compliance with exercise was 86%. These results suggest that exercise training may improve exercise capacity of CCS with subclinical cardiomyopathy.
childhood cancer survivor; exercise training; strength training; anthracyclines; cardiomyopathy
To evaluate associations between prepregnancy lifestyle factors, psychological distress and adverse pregnancy outcomes among female survivors of childhood cancer.
We examined pregnancies of 1,192 female participants from the Childhood Cancer Survivor Study. Generalized linear models, adjusted for age at diagnosis, age at pregnancy, parity, and education were used to calculate the odds ratio (OR) and confidence interval (CI) for associations between prepregnancy inactivity, overweight or obese status, smoking status, risky drinking, psychological distress and pregnancy outcomes. Interactions between lifestyle factors, psychological distress, type of cancer and cancer treatment were assessed in multivariable models.
The median age of study participants at the beginning of pregnancy was 28 years (range: 14–45). Among 1,858 reported pregnancies, there were 1,300 singleton live births (310 were preterm), 21 stillbirths, 397 miscarriages, and 140 medical abortions. Prepregnancy physical inactivity, risky drinking, distress and depression were not associated with any pregnancy outcomes. Compared to those who had never smoked, survivors with > 5 pack-years smoking history had a higher risk for miscarriage among those treated with > 2.5 Gy uterine radiation (OR: 53.9; 95% CI: 2.2, 1,326.1) than among those treated with ≤ 2.5 Gy uterine radiation (OR: 1.9; 95% CI: 1.2, 3.0). There was a significant interaction between smoking and uterine radiation (Pinteraction = 0.01).
While most lifestyle factors and psychological distress were not predictive of adverse pregnancy outcomes, the risk for miscarriage was significantly increased among survivors exposed to > 2.5 Gy uterine radiation who had a history of smoking.
pregnancy; childhood cancer survivors; uterine radiation; smoking; lifestyle
Intra-operative tumor spill increases the risk of local recurrence of Wilms tumor, and adversely impacts relapse-free (RFS) and overall survival (OS) rates.
Surgical checklists, operative notes, institutional pathology reports, central pathology review and flow sheets of 602 patients registered between August 1986 and September 1994 on National Wilms Tumor Study – 4 as randomized, followed or switched and coded as Final Stage II, favorable histology (FH) were reviewed. RFS and OS were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated using the Cox model and tested for statistical significance by the log-rank test.
Four hundred ninety-nine patients were found after review to have stage II, FH Wilms tumor. The eight-year RFS percentages were 85.0% (95% confidence interval (CI) – 81.1%, 88.1%) for those with no spill compared to 75.7% (65.8%, 83.2%) for those with spill. The eight-year OS percentages were 95.6% (93.1%, 97.3%) for those with no spill compared to 90.3% (82.2%, 94.9%) for those with spill. The HR for relapse among those with spill was 1.55 ((95%CI – 0.97,2.51), p = 0.067) and the HR for death was 1.94 ((0.92,4.09), p = 0.077).
RFS and OS were lower for patients who had intra-operative tumor spill. The majority of NWTS stage II, FH patients with intra-operative tumor spill have an overall excellent outcome when treated with two drug chemotherapy (vincristine and actinomycin D) and no abdominal irradiation.
Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses.
We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS)outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike’s Information Criterion (AIC).
The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure.
The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure.
late effects of cancer treatment; chemotherapy; long term survival; cyclophosphamide; alkylating agent; alkylating agent dose score
Standard treatment of pulmonary metastasis in patients with Wilms tumor (WT) includes 12 Gy radiation therapy (RT) to the entire chest. The risk of breast cancer (BC) in a large cohort of female survivors of WT has not previously been reported.
2,492 female participants in National Wilms Tumor Studies 1–4 (1969–1995) were followed from age 15 through mid 2013 for incident BC. Median age at last contact was 27.3 years. We calculated cumulative risk at age 40 (CR40), hazard ratios (HR) by Cox regression, standardized incidence ratios (SIR) relative to US population rates and [shown in brackets] 95% confidence intervals.
Numbers of survivors with invasive BC divided by numbers at risk were 16/369 (CR40=14.8% [8.7–24.5]) for women who received chest RT for metastatic WT, 10/894 (CR40=3.1% [1.3–7.41]) for those who received only abdominal RT and 2/1,229 (CR40=0.3% [0.0–2.3]) for those who received no RT. The SIRs for these three groups were 27.6 [16.1–44.2] based on 5,010 person-years (PY) of follow-up, 6.0 [2.9,11.0] based on 13,185 PY, and 2.2 [0.3,7.8] based on 13,560 PY, respectively. The risk was high regardless of chest RT among women diagnosed with WT at age 10 or later, with 9/90 developing BC (CR40=13.5% [5.6–30.6], SIR=23.6 [10.8–44.8], PY=1,463).
Female WT survivors treated with chest RT had high risk of early BC, with nearly 15% developing invasive disease by age 40. Current guidelines that recommend screening only survivors receiving ≥20 Gy RT to the chest might be re-evaluated.
Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality.
Participants included 1,922 CCS at least 10 years from original cancer diagnosis (men, 50.3%; mean age, 33.6 ± 8.1 years) and a comparison population of 341 participants without cancer histories. Prefrailty and frailty were defined as two and ≥ three of the following conditions: low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Morbidity was defined as grade 3 to 4 chronic conditions (Common Terminology Criteria for Adverse Events version 4.0). Fisher's exact tests were used to compare, by frailty status, percentages of those with morbidity. In a subset of 162 CCS who returned for a second visit, Poisson regression was used to evaluate associations between frailty and new onset morbidity. Cox proportional hazards regression was used to evaluate associations between frailty and death.
The prevalence of prefrailty and frailty were 31.5% and 13.1% among women and 12.9% and 2.7% among men, respectively, with prevalence increasing with age. Frail CCS were more likely than nonfrail survivors to have a chronic condition (82.1% v 73.8%). In models adjusted for existing chronic conditions, baseline frailty was associated with risk of death (hazard ratio, 2.6; 95% CI, 1.2 to 6.2) and chronic condition onset (relative risk, 2.2; 95% CI, 1.2 to 4.2).
The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.
Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer.
Many Childhood Cancer Survivor Study (CCSS) participants are at increased risk for obesity. The etiology of their obesity is likely multifactorial but not well understood.
Patients and Methods
We evaluated the potential contribution of demographic, lifestyle, treatment, and intrapersonal factors and self-reported pharmaceutical use to obesity (body mass index ≥ 30 kg/m2) among 9,284 adult (> 18 years of age) CCSS participants. Independent predictors were identified using multivariable regression models. Interrelationships were determined using structural equation modeling (SEM).
Independent risk factors for obesity included cancer diagnosed at 5 to 9 years of age (relative risk [RR], 1.12; 95% CI, 1.01 to 1.24; P = .03), abnormal Short Form–36 physical function (RR, 1.19; 95% CI, 1.06 to 1.33; P < .001), hypothalamic/pituitary radiation doses of 20 to 30 Gy (RR, 1.17; 95% CI, 1.05 to 1.30; P = .01), and paroxetine use (RR, 1.29; 95% CI, 1.08 to 1.54; P = .01). Meeting US Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82 to 0.97; P = .01) and a medium amount of anxiety (RR, 0.86; 95% CI, 0.75 to 0.99; P = .04) reduced the risk of obesity. Results of SEM (N = 8,244; comparative fit index = 0.999; Tucker Lewis index = 0.999; root mean square error of approximation = 0.014; weighted root mean square residual = 0.749) described the hierarchical impact of the direct predictors, moderators, and mediators of obesity.
Treatment, lifestyle, and intrapersonal factors, as well as the use of specific antidepressants, may contribute to obesity among survivors. A multifaceted intervention, including alternative drug and other therapies for depression and anxiety, may be required to reduce risk.
This study was undertaken to evaluate the incidence of pulmonary disease among patients treated with radiation therapy (RT) for pulmonary metastases (PM) from Wilms tumor (WT).
Patients and Methods
We reviewed records of 6,449 patients treated on National Wilms Tumor Studies -1, -2, -3, and -4 whose flow sheets or annual status reports documented one of several pulmonary conditions. Cases were fully evaluable if pulmonary function test (PFT) results were available, pulmonary fibrosis was identified on a chest radiograph or was listed as the primary or a contributing factor to death. Partially evaluable cases were those for whom PFT results could not be obtained. We evaluated the relationship between RT factors and the occurrence of pulmonary disease using hazard ratios (HR) and cumulative incidence, treating death as a competing risk.
Sixty-four fully evaluable and 16 partially evaluable cases of pulmonary disease were identified. The cumulative incidence of pulmonary disease at 15 years since WT diagnosis was 4.0% (95% confidence interval (CI) 2.6-5.4%) among fully evaluable and 4.8% (95% CI 3.3-6.4%) among fully and partially evaluable patients who received lung RT for PM at initial diagnosis. Rates of pulmonary disease were substantially higher among those who received lung RT for PM present at initial diagnosis or relapse compared to those who received no RT or only abdominal RT (hazard ratio (HR) 30.2, 95% CI 16.9-53.9).
The risk of pulmonary disease must be considered in evaluating the risk:benefit ratio of lung RT for the management of PM from WT.
Wilms tumor; pulmonary disease; radiation therapy; actinomycin D; doxorubicin
A high proportion of pediatric cancer patients are now surviving into adulthood, but are at increased risk for late morbidity and premature mortality related to their diagnosis and therapeutic exposures. Little is known about the potential success of recruiting adult survivors of childhood cancer into research projects that would require a risk-based health evaluation within a clinical setting.
Pediatric cancer survivors and siblings eligible for the current study were Childhood Cancer Survivor Study participants who lived within 100 miles of one of five Consortium for Pediatric Intervention Research institutions, regardless of where they were initially diagnosed and treated. A short survey was mailed to 829 survivors and 373 siblings to identify factors that predict interest, potential barriers, and motivators, to participation in research including a risk-based clinical evaluation.
Overall, 92% of survivors responding to the survey were very interested/interested in participating in a research study requiring a visit to a local hospital clinic. Siblings of survivors were less interested than survivors in participating in such a study, with only 78% indicating that they were very interested/ interested. Potential motivators to participation included visiting their treating hospital and receiving health information. The primary barrier to participation was related to taking time off from work.
This study demonstrates that a subgroup of survivors would be willing to return to a long-term follow-up center to participate in intervention-based research. Identified motivating factors and perceived barriers need to be considered in determining the feasibility, design and execution of future research.
pediatric cancer; survivors; recruitment; risk-based evaluation; cohort study
Complete resection of lung metastases improves survival in patients with osteosarcoma. We evaluated the long-term effect of metastasectomy on pulmonary function of patients treated for osteosarcoma during childhood.
We reviewed the medical records of patients who had pulmonary function tests (PFTs) following metastasectomy for osteosarcoma. Patient, tumor, and treatment variables were abstracted along with PFTs. PFTs were recorded as a percentage of predicted value and were classified as abnormal for FVC <80%, FEV1 <80%, TLC <75%, and DLCOcorr <75%.
Twenty-one patients had PFTs performed during follow-up. Mean age at diagnosis of osteosarcoma was 13.2±4.7 years. Fifteen patients had a single thoracotomy, and 6 patients had ≥ 2 thoracotomies (range, 2–6). Eighty lesions were resected. Nine patients had ≤ 2 lesions resected and 12 patients had >2 lesions (range, 3–12) resected. Mean time from the last surgical procedure to measurement of PFTs was 20.3±9.0years. TLC was abnormal for 28.6%, DLCOcorr for 47.4%, FVC for 40%, and FEV1 for 47.6% of the cohort members. Individual PFTs were abnormal in 13.3% (TLC) to 46.7% (DLCOcorr) of patients who had one thoracotomy and in 50.0% (DLCOcorr) to 66.7% (FEV1, TLC) of patients with ≥two thoracotomies. The number of thoracotomies was associated with abnormal TLC (p=0.03).
Patients who underwent pulmonary metastasectomy for osteosarcoma as children often had abnormal PFTs on long-term follow up, but the reduction in lung volumes and DLCOcorr was relatively mild. Multiple thoracotomies predicted greater impairment of pulmonary function.
Stage III designation in NWTS-5 (National Wilms Tumor Study–5) was determined by four pathologic criteria: positive lymph nodes (LNs), peritoneal implants, residual disease, and tumor rupture. The objective of this study was to determine the prognostic significance of each of the stage III criteria.
Patients and Methods
Children with stage III Wilms tumor (WT) treated in NWTS-5 were assessed for event-free (EFS) and overall survival (OS). Sites of relapse and molecular status of tumors are reported. EFS and OS are reported 8 years after diagnosis.
There were 569 patients with local stage III favorable-histology (FH) WT in this analysis, of whom 109 had overall stage IV disease. LN involvement alone was the most frequent criterion for stage III designation (38%), followed by microscopic residual disease alone (20%), microscopic residual disease and LN involvement (14%), and spill or soilage alone (9%). The 8-year EFS and OS estimates for all patients with local stage III FHWT were 82% and 91%, respectively. Multivariate analysis demonstrated that both LN involvement (relative risk, 1.89; P = .005) and microscopic residual disease (relative risk, 1.87; P = .007) were predictive of EFS, and OS results were similar. There was no apparent difference in pattern of relapse according to stage III subtype. The rate of loss of heterozygosity was higher (6%) for those with positive LNs than for those without (2%; P = .05).
LN involvement and microscopic residual are the stage III criteria highly predictive of EFS and OS for patients with stage III FHWT. It is possible that in future studies, patients with different stage III criteria may receive different therapies.
As more young female patients with cancer survive their primary disease, concerns about reproductive health related to primary therapy gain relevance. Cancer therapy can often affect reproductive organs, leading to impaired pubertal development, hormonal regulation, fertility, and sexual function, affecting quality of life.
The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer (COG-LTFU Guidelines) are evidence-based recommendations for screening and management of late effects of therapeutic exposures. The guidelines are updated every 2 years by a multidisciplinary panel based on current literature review and expert consensus.
This review summarizes the current task force recommendations for the assessment and management of female reproductive complications after treatment for childhood, adolescent, and young adult cancers. Experimental pretreatment as well as post-treatment fertility preservation strategies, including barriers and ethical considerations, which are not included in the COG-LTFU Guidelines, are also discussed.
Ongoing research will continue to inform COG-LTFU Guideline recommendations for follow-up care of female survivors of childhood cancer to improve their health and quality of life.
Effective vaccination is now available to prevent human papillomavirus (HPV), the most common sexually transmitted infection and cause of cervical cancer. This study aimed to estimate the prevalence of HPV vaccination among childhood cancer survivors and identify factors associated with HPV vaccine initiation and completion. Mothers of daughters aged 9–17 years with/without a history of childhood cancer (n = 235, Mage= 13.2 years, SD= 2.69; n = 70, Mage= 13.3 years, SD=2.47, respectively) completed surveys querying HPV vaccination initiation and completion along with socio-demographic, medical, HPV knowledge and communication, and health belief factors, which may relate to vaccination outcomes. Multivariate logistic regression was utilized to identify factors which associate with HPV vaccination initiation and completion. Among cancer survivors, 32.6% initiated and 17.9% completed the 3-dose vaccine series, whereas 34.3% and 20.0% of controls initiated and completed, respectively. Univariate analyses indicated no differences between cancer/no cancer groups on considered risk factors. Among all participants, multivariate logistic regression analyses found vaccine initiation associated with older age of daughter and physician recommendation, while increased perceived barriers associated with a decreased likelihood of initiation (all Ps < .05). Among those having initiated, risk factors for non-completion included being non-white, increased perceived severity of HPV, and increased perceived barriers to vaccination (all Ps < .05). A minority of adolescents surviving childhood cancer have completed vaccination despite their increased risk for HPV-related complication. These results inform the prioritization of strategies to be included in vaccine promotion efforts.
To determine the prevalence of pulmonary hypertension, a late effect of cancer therapy not previously identified in aging survivors of childhood cancer, and associations with chest-directed radiation therapy (RT) and measures of current cardiac function, lung function, and exercise capacity.
Patients and Methods
Cross-sectional evaluation of 498 survivors at a median age of 38.0 years (range, 20.0 to 59.0 years) and a median of 27.3 years (range, 12.2 to 46.0 years) from primary cancer diagnosis was performed. Abnormal tricuspid regurgitant jet velocity (TRV) was defined as more than 2.8 m/s by Doppler echocardiography.
Increased TRV was identified in 25.2% of survivors who received chest-directed RT and 30.8% of those who received more than 30 Gy. In multivariable models, increased TRV was associated with increasing dose of RT (1 to 19.9 Gy: odds ratio [OR], 2.09; 95% CI, 0.63 to 6.96; 20 to 29.9 Gy: OR, 3.46; 95% CI, 1.59 to 7.54; ≥ 30 Gy: OR, 4.54; 95% CI, 1.77 to 11.64 compared with no RT; P for trend < .001), body mass index more than 40 kg/m2 (OR, 3.89; 95% CI, 1.46 to 10.39), and aortic valve regurgitation (OR, 5.85; 95% CI, 2.05 to 16.74). Survivors with a TRV more than 2.8 m/s had increased odds (OR, 5.20; 95% CI, 2.5 to 11.0) of severe functional limitation on a 6-minute walk compared with survivors with a TRV ≤ 2.8 m/s.
A substantial number of adult survivors of childhood cancer who received chest-directed RT have an increased TRV and may have pulmonary hypertension as a result of both direct lung injury and cardiac dysfunction. Longitudinal follow-up and confirmation by cardiac catheterization are warranted.
Long-term survivors of childhood Hodgkin lymphoma (HL) are at risk for cardiopulmonary complications and CNS stroke, although neurocognitive function has not been previously examined. The aim of this study was to examine neurocognitive and brain imaging outcomes in adult survivors of childhood HL.
Patients and Methods
In all, 62 adult survivors (mean age, 42.2 years; standard deviation [SD], 4.77; mean age at diagnosis, 15.1 years; SD, 3.30) were identified by stratified random selection from a large cohort treated with either high-dose (≥ 30 Gy) thoracic radiation (n = 38) or lower-dose (< 30 Gy) thoracic radiation combined with anthracycline (n = 24). Patients underwent neurocognitive evaluations, brain magnetic resonance imaging (MRI), echocardiograms, pulmonary function tests, and physical examinations.
Compared with national age-adjusted norms, HL survivors demonstrated lower performance on sustained attention (P = .004), short-term memory (P = .001), long-term memory (P = .006), working memory (P < .001), naming speed (P < .001), and cognitive fluency (P = .007). MRI revealed leukoencephalopathy in 53% of survivors, and 37% had evidence of cerebrovascular injury. Higher thoracic radiation dose was associated with impaired cardiac diastolic function (E/E′; ratio of peak mitral flow velocity of early rapid filling [E] to early diastolic velocity of the mitral annulus [E′]; P = .003), impaired pulmonary function (diffusing capacity of lungs for carbon monoxide [DLcocorr; P = .04), and leukoencephalopathy (P = .02). Survivors with leukoencephalopathy demonstrated reduced cognitive fluency (P = .001). Working memory impairment was associated with E/E′, although impaired sustained attention and naming speed were associated with DLcocorr. Neurocognitive performance was associated with academic and vocational functioning.
These results suggest that adult long-term survivors of childhood HL are at risk for neurocognitive impairment, which is associated with radiologic indices suggestive of reduced brain integrity and which occurs in the presence of symptoms of cardiopulmonary dysfunction.
To compare two-dimensional (2D) echocardiography, the current method of screening for treatment-related cardiomyopathy recommended by the Children's Oncology Group Guidelines, to cardiac magnetic resonance (CMR) imaging, the reference standard for left ventricular (LV) function.
Patients and Methods
Cross-sectional, contemporaneous evaluation of LV structure and function by 2D and three-dimensional (3D) echocardiography and CMR imaging in 114 adult survivors of childhood cancer currently median age 39 years (range, 22 to 53 years) exposed to anthracycline chemotherapy and/or chest-directed radiation therapy.
In this survivor population, 14% (n = 16) had an ejection fraction (EF) less than 50% by CMR. Survivors previously undiagnosed with cardiotoxicity (n = 108) had a high prevalence of EF (32%) and cardiac mass (48%) that were more than two standard deviations below the mean of normative CMR data. 2D echocardiography overestimated the mean EF of this population by 5%. Compared with CMR, 2D echocardiography (biplane method) had a sensitivity of 25% and a false-negative rate of 75% for detection of EF less than 50%, although 3D echocardiography had 53% and 47%, respectively. Twelve survivors (11%) had an EF less than 50% by CMR but were misclassified as ≥ 50% (range, 50% to 68%) by 2D echocardiography (biplane method). Detection of cardiomyopathy was improved (sensitivity, 75%) by using a higher 2D echocardiography cutoff (EF < 60%) to detect an EF less than 50% by the reference standard CMR.
CMR identified a high prevalence of cardiomyopathy among adult survivors previously undiagnosed with cardiac disease. 2D echocardiography demonstrated limited screening performance. In this high-risk population, survivors with an EF 50% to 59% by 2D echocardiography should be considered for comprehensive cardiac assessment, which may include CMR.
Children with cancer receive mutagenic treatments, which raises concern about the potential transmissibility of germline damage to their offspring. This question has been inadequately studied to date because of a lack of detailed individual treatment exposure assessment such as gonadal radiation doses.
Within the Childhood Cancer Survivor Study, we performed a retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female childhood cancer survivors. We quantified chemotherapy with alkylating agents and radiotherapy doses to the testes and ovaries and related these exposures to risk of congenital anomalies using logistic regression.
One hundred twenty-nine children had at least one anomaly (prevalence = 2.7%). For children whose mothers were exposed to radiation or alkylating agents versus neither, the prevalence of anomalies was 3.0% versus 3.5% (P = .51); corresponding figures were 1.9% versus 1.7% (P = .79) for the children of male survivors. Neither ovarian radiation dose (mean, 1.19 Gy; odds ratio [OR] = 0.59; 95% CI, 0.20 to 1.75 for 2.50+ Gy) nor testicular radiation dose (mean, 0.48 Gy; OR = 1.01; 95% CI, 0.36 to 2.83 for 0.50+ Gy) was related to risk of congenital anomalies. Treatment with alkylating agents also was not significantly associated with anomalies in the children of male or female survivors.
Our findings offer strong evidence that the children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parent's exposure to mutagenic cancer treatments. This information is important for counseling cancer survivors planning to have children.
To evaluate the effect of hypothalamic/pituitary radiation dose on the occurrence of first pregnancy
Retrospective cohort study of childhood cancer five-year survivors (CCS) diagnosed between 1970 and 1986 prior to 21 years of age at one of 26 North American pediatric cancer treatment centers
3619 female CCS who participated in the Childhood Cancer Survivor Study and received no/scatter (≤ 0.1 Gy) radiation to the ovaries and 2081 female siblings (Sibs) of the participants
Main Outcome Measure(s)
Self-reported pregnancy events
As a group CCS were as likely to report being pregnant as Sibs (Hazard Ratio (HR), 1.07; 95% Confidence Interval (95%CI), 0.97 to 1.19). Multivariable models showed a significant decrease in the risk of pregnancy with HPT RT doses ≥ 22 Gy compared with those CCS receiving no HPT RT.
These results support the hypothesis that exposures of 22 to 27 Gy HPT RT may be a contributing factor to infertility among female CCS.
childhood cancer survivor; hypothalamic irradiation; pituitary irradiation; alkylating agent; pregnancy
This study was undertaken to evaluate the effect of prior treatment with radiation therapy or chemotherapy for unilateral Wilms tumor (WT) diagnosed during childhood on pregnancy complications, birth weight, and the frequency of congenital malformations in live-born offspring.
Patients and Methods
We reviewed pregnancy outcomes among female survivors and partners of male survivors of WT treated on National Wilms Tumor Studies 1, 2, 3, and 4 by using a maternal questionnaire and a review of both maternal and offspring medical records.
We received reports of 1,021 pregnancies with duration of 20 weeks or longer, including 955 live-born singletons, for whom 700 sets of maternal and offspring medical records were reviewed. Rates of hypertension complicating pregnancy (International Classification of Diseases [ICD] code 642), early or threatened labor (ICD-644) and malposition of the fetus (ICD-652) increased with increasing radiation dose in female patients. The percentages of offspring weighing less than 2,500 g at birth and of those having less than 37 weeks of gestation also increased with dose. There was no significant trend with radiation dose in the number of congenital anomalies recorded in offspring of female patients.
Women who receive flank radiation therapy as part of the treatment for unilateral WT are at increased risk of hypertension complicating pregnancy, fetal malposition, and premature labor. The offspring of these women are at risk for low birth weight and premature (ie, < 37 weeks gestation) birth. These risks must be considered in the obstetrical management of female survivors of WT.