Risk-stratified therapy, which modifies treatment on the basis of clinical and biologic features, has improved 5-year overall survival of childhood acute lymphoblastic leukemia (ALL) to 90%, but its ...impact on long-term toxicity remains unknown.
We assessed all-cause and health-related late mortality (including late effects of cancer therapy), subsequent malignant neoplasms (SMNs), chronic health conditions, and neurocognitive outcomes among 6,148 survivors of childhood ALL (median age, 27.9 years; range, 5.9-61.9 years) diagnosed between 1970 and 1999. Therapy combinations and treatment intensity defined 6 groups: 1970s-like (70s), standard- or high-risk 1980s-like (80sSR, 80sHR) and 1990s-like (90sSR, 90sHR), and relapse/transplantation (R/BMT). Cumulative incidence, standardized mortality ratios, and standardized incidence ratios were compared between treatment groups and with the US population.
Overall, 20-year all-cause late mortality was 6.6% (95% CI, 6.0 to 7.1). Compared with 70s, 90sSR and 90sHR experienced lower health-related late mortality (rate ratio 95% CI: 90sSR, 0.2 0.1 to 0.4; 90sHR, 0.3 0.1 to 0.7), comparable to the US population (standardized mortality ratio 95% CI: 90sSR, 1.3 0.8 to 2.0; 90sHR, 1.7 0.7 to 3.5). Compared with 70s, 90sSR had a lower rate of SMN (rate ratio 95% CI, 0.3 0.1 to 0.6) that was not different from that of the US population (standardized incidence ratio 95% CI, 1.0 0.6 to 1.6). The 90sSR group had fewer severe chronic health conditions than the 70s (20-year cumulative incidence 95% CI, 11.0% 9.7% to 12.3%
22.5% 19.4% to 25.5%) and a lower prevalence of impaired memory (prevalence ratio 95% CI, 0.7 0.6 to 0.9) and task efficiency (0.5 0.4 to 0.7).
Risk-stratified therapy has reduced late morbidity and mortality among contemporary survivors of standard-risk ALL, represented by 90sSR. Health-related late mortality and SMN risks among 5-year survivors of contemporary, standard-risk childhood ALL are comparable to the general population.
Late effects and frontline treatment selection for children with non-Hodgkin lymphoma Ehrhardt, Matthew J.; Dixon, Stephanie B.; Belsky, Jennifer ...
Baillière's best practice and research in clinical haematology/Baillière's best practice & research. Clinical haematology,
March 2023, 2023-03-00, 20230301, Letnik:
36, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Approximately 1 in 640 adults between 20 and 40 years of age is a survivor of childhood cancer. However, survival has often come at the expense of increased risk of long-term complications, including ...chronic health conditions and higher mortality rates. Similarly, long-term survivors of childhood non-Hodgkin lymphoma (NHL) experience significant morbidity and mortality related to prior cancer treatments, highlighting the importance of primary and secondary prevention strategies to mitigate late toxicity. As a result, effective treatment regimens for pediatric NHL have evolved to reduce both short- and long-term toxicity through cumulative dose reductions and elimination of radiation. The establishment of effective regimens facilitates shared decision-making opportunities for frontline treatment selection that considers efficacy, acute toxicity, convenience, and late effects of treatments. The current review seeks to merge current frontline treatment regimens with survivorship guidelines to enhance understanding of potential long-term health risks to facilitate best treatment practices.
Abstract
Background
The purpose was to examine associations between treatment and chronic health conditions with neurocognitive impairment survivors of acute lymphoblastic leukemia (ALL) treated with ...chemotherapy only.
Methods
This cross-sectional study included 1207 ALL survivors (54.0% female; mean age 30.6 years) and 2273 siblings (56.9% female; mean age 47.6 years), who completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire. Multivariable logistic regression compared prevalence of neurocognitive impairment between survivors and siblings by sex. Associations between neurocognitive impairment with treatment exposures and chronic conditions (graded according to Common Terminology Criteria for Adverse Events) were also examined. Statistical tests were 2-sided.
Results
Relative to same-sex siblings, male and female ALL survivors reported increased prevalence of impaired task efficiency (males: 11.7% vs 16.9%; adjusted odds ratio OR = 1.89, 95% confidence interval CI = 1.31 to 2.74; females: 12.5% vs 17.6%; OR = 1.50, 95% CI = 1.07 to 2.14), as well as impaired memory (males: 11.6% vs 19.9%, OR = 1.89, CI = 1.31 to 2.74; females: 14.78% vs 25.4%, OR = 1.96, 95% CI = 1.43 to 2.70, respectively). Among male survivors, impaired task efficiency was associated with 2-4 neurologic conditions (OR = 4.33, 95% CI = 1.76 to 10.68) and with pulmonary conditions (OR = 4.99, 95% CI = 1.51 to 16.50), and impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR = 1.68, 95% CI = 1.16 to 2.46) and with exposure to dexamethasone (OR = 2.44, 95% CI = 1.19 to 5.01). In female survivors, grade 2-4 endocrine conditions were associated with higher risk of impaired task efficiency (OR = 2.19, 95% CI = 1.20 to 3.97) and memory (OR = 2.26, 95% CI = 1.31 to 3.92).
Conclusion
Neurocognitive impairment is associated with methotrexate, dexamethasone, and chronic health conditions in a sex-specific manner, highlighting the need to investigate physiological mechanisms and monitor impact through survivorship.
5-year survival after childhood cancer does not fully describe life-years lost due to childhood cancer because there are a large number of deaths occurring beyond 5-years (late mortality) related to ...cancer and cancer treatment. Specific causes of health-related (non-recurrence, non-external) late mortality and risk reduction through modifiable lifestyle and cardiovascular risk factors are not well described. Through using a well-characterised cohort of 5-year survivors of the most common childhood cancers, we evaluated specific health-related causes of late mortality and excess deaths compared with the general US population and identified targets to reduce future risk.
In this multi-institutional, hospital-based, retrospective cohort study, late mortality (death ≥5 years from diagnosis) and specific causes of death were evaluated in 34 230 5-year survivors of childhood cancer diagnosed at an age younger than 21 years from 1970 to 1999 at 31 institutions in the USA and Canada; median follow-up from diagnosis was 29 years (range 5–48) in the Childhood Cancer Survivor Study. Demographic, self-reported modifiable lifestyle (ie, smoking, alcohol, physical activity, and BMI) and cardiovascular risk factors (ie, hypertension, diabetes, and dyslipidaemia) associated with health-related mortality (which excludes death from primary cancer and external causes and includes death from late effects of cancer therapy) were evaluated.
40-year cumulative all-cause mortality was 23·3% (95% CI 22·7–24·0), with 3061 (51·2%) of 5916 deaths from health-related causes. Survivors 40 years or more from diagnosis experienced 131 excess health-related deaths per 10 000 person-years (95% CI 111–163), including those due to the top three causes of health-related death in the general population: cancer (absolute excess risk per 10 000 person-years 54, 95% CI 41–68), heart disease (27, 18–38), and cerebrovascular disease (10, 5–17). Healthy lifestyle and absence of hypertension and diabetes were each associated with a 20–30% reduction in health-related mortality independent of other factors (all p values ≤0·002).
Survivors of childhood cancer are at excess risk of late mortality even 40 years from diagnosis, due to many of the leading causes of death in the US population. Modifiable lifestyle and cardiovascular risk factors associated with reduced risk for late mortality should be part of future interventions.
US National Cancer Institute and the American Lebanese Syrian Associated Charities.
Background
Survivors of childhood cancer are at risk of neurocognitive impairment, emotional distress, and poor health‐related quality of life (HRQOL); however, the effect of race/ethnicity is ...understudied. The objective of this study was to identify race/ethnicity‐based disparities in neurocognitive, emotional, and HRQOL outcomes among survivors of childhood cancer.
Methods
Self‐reported measures of neurocognitive function, emotional distress (the Brief Symptom Inventory‐18), and HRQOL (the Medical Outcomes Study Short Form‐36 health survey) were compared between minority (Hispanic, n = 821; non‐Hispanic black NHB, n = 600) and non‐Hispanic white (NHW) (n = 12,287) survivors from the Childhood Cancer Survivor Study (median age, 30.9 years; range, 16.0‐54.1 years). By using a sample of 3055 siblings, the magnitude of same‐race/same‐ethnicity survivor‐sibling differences was compared between racial/ethnic groups, adjusting for demographic and treatment characteristics and current socioeconomic status (SES).
Results
No clear pattern of disparity in neurocognitive outcomes by race/ethnicity was observed. The magnitude of the survivor‐sibling difference in the mean score for depression was greater in Hispanics than in NHWs (3.59 vs 1.09; P = .004). NHBs and Hispanics had greater survivor‐sibling differences in HRQOL than NHWs for mental health (NHBs: −5.78 vs −0.69; P = .001; Hispanics: −3.87 vs −0.69; P = .03), and social function (NHBs: −7.11 vs −1.47; P < .001; Hispanics: −5.33 vs −1.47; P = .001). NHBs had greater survivor‐sibling differences in physical subscale scores for HRQOL than NHWs. In general, the findings were not attenuated by current SES.
Conclusions
Although no pattern of disparity in neurocognitive outcomes was observed, differences across many HRQOL outcomes among minorities compared with NHWs, not attenuated by current SES, were identified. This suggests that further research into environmental and sociocultural factors during and immediately after treatment is needed.
Disparities across many domains of health‐related quality of life among minority survivors of childhood cancer compared with non‐Hispanic whites are identified and are not fully explained by socioeconomic status. Fortunately, no pattern of differences in neurocognitive outcomes by race/ethnicity was identified.
Given the relatively small population of Asians or Pacific Islanders (API) in the United States, studies describing long-term outcomes in API survivors of childhood cancer are limited. This study ...compared functional outcomes between API versus non-Hispanic White (NHW) survivors.
This study included 203 API 5-year survivors age at follow-up: 29.2 (SD = 6.3) years and 12,186 NHW survivors age at follow-up 31.5 (SD = 7.3) years from the Childhood Cancer Survivor Study. Self-reported functional outcomes of neurocognitive function, emotional distress, quality of life, and social attainment were compared between the two groups using multivariable regression, adjusted for sex, age at diagnosis and evaluation, cancer diagnosis, and neurotoxic treatment.
No statistically significant race/ethnicity-based differences were identified in neurocognitive and emotional measures. API survivors reported, on average, less bodily pain than NHW survivors mean 54.11 (SD = 8.98) vs. 51.32 (SD = 10.12);
< 0.001. NHW survivors were less likely to have attained at least a college degree than API survivors OR = 0.50; 95% confidence interval (CI) = 0.34-0.73. API survivors were more likely than NHW survivors to be never-married (OR = 2.83; 95% CI = 1.93-4.13) and to live dependently (OR = 3.10; 95% CI = 2.02-4.74). Older age (>45 years), brain tumor diagnosis, and higher cranial radiation dose were associated with poorer functional outcomes in API survivors (all,
< 0.05).
We observed differences in social attainment between API and NHW survivors, although statistically significant differences in neurocognitive and emotional outcomes were not identified.
Future studies should evaluate whether racial/ethnic differences in environmental and sociocultural factors may have differential effects on health and functional outcomes.
Adult survivors of childhood cancer have high rates of obesity, which, in combination with the cardiotoxic effects of specific cancer therapies, places them at high risk for cardiovascular morbidity. ...Here we show the contribution of genetic risk scores (GRSs) to increase prediction of those survivors of childhood cancer who are at risk for severe obesity (body mass index ≥40 kg m
) as an adult. Among 2,548 individuals of European ancestry from the St. Jude Lifetime Cohort Study who were 5-year survivors of childhood cancer, the GRS was found to be associated with 53-fold-higher odds of severe obesity. Addition of GRSs to risk prediction models based on cancer treatment exposures and lifestyle factors significantly improved model prediction (area under the curve increased from 0.68 to 0.75, resulting in the identification of 4.3-times more high-risk survivors), which was independently validated in 6,064 individuals from the Childhood Cancer Survivor Study. Genetic predictors improve identification of patients who could benefit from heightened surveillance and interventions to mitigate the risk of severe obesity and associated cardio-metabolic complications.
The effect of the increasing lifetime burden of non-major cardiovascular conditions on risk for a subsequent major adverse cardiovascular event among survivors of childhood cancer has not been ...assessed. We aimed to characterise the prevalence of major adverse cardiovascular events and their association with the cumulative burden of non-major adverse cardiovascular events in childhood cancer survivors.
This is a longitudinal cohort study with participant data obtained from an ongoing cohort study at St Jude Children's Research Hospital: the St Jude Lifetime Cohort Study (SJLIFE). Prospective clinical follow-up was of 5-year survivors of childhood cancer who were diagnosed when aged younger than 25 years from 1962 to 2012. Age-frequency, sex-frequency, and race-frequency matched community-control participants completed a similar one-time clinical assessment. 22 cardiovascular events were graded using a St Jude Children's Research Hospital-modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Cumulative incidence and burden of the primary outcome of major adverse cardiovascular events (cardiomyopathy, myocardial infarction, stroke, and other cardiovascular-related mortality) were estimated. Rate ratios (RR) of the association of major adverse cardiovascular events with 22 non-major adverse cardiovascular events were estimated using multivariable piecewise-exponential regression adjusting for attained age, age at diagnosis, sex, race and ethnicity, treatment era, diagnosis of diabetes, and exposure to cardiotoxic cancer therapies. The St Jude Lifetime Cohort study is registered with ClinicalTrials.gov, NCT00760656, and is ongoing.
9602 5-year survivors of childhood cancer, and 737 community controls were included in the longitudinal follow-up (from Sept 13, 2007, to Dec 17, 2021). The median follow-up was 20·3 years (IQR 12·0–31·4) from the date of primary cancer diagnosis (4311 44.9% were females). By the age of 50 years (analysis stopped at age 50 years due to the low number of participants older than that age), the cumulative incidence of major adverse cardiovascular events among survivors was 17·7% (95% CI 15·9–19·5) compared with 0·9% (0·0–2·1) in the community controls. The cumulative burden of major adverse cardiovascular events in survivors was 0·26 (95% CI 0·23–0·29) events per survivor compared with 0·009 (0·000–0·021) events per community control participant. Increasing cumulative burden of grade 1–4 non-major adverse cardiovascular events was associated with an increased future risk of major adverse cardiovascular events (one condition: RR 4·3, 95% CI 3·1–6·0; p<0·0001; two conditions: 6·6, 4·6–9·5; p<0·0001; and three conditions: 7·7, 5·1–11·4; p<0·0001). Increased risk for major adverse cardiovascular events was observed with specific subclinical conditions (eg, grade 1 arrhythmias RR 1·5, 95% CI 1·2–2·0; p=0·0017), grade 2 left ventricular systolic dysfunction (2·2, 1·6–3·1; p<0·0001), grade 2 valvular disorders (2·2, 1·2–4·0; p=0·013), but not grade 1 hypercholesterolaemia, grade 1–2 hypertriglyceridaemia, or grade 1–2 vascular stenosis.
Among an ageing cohort of survivors of childhood cancer, the accumulation of non-major adverse cardiovascular events, including subclinical conditions, increased the risk of major adverse cardiovascular events and should be the focus of interventions for early detection and prevention of major adverse cardiovascular events.
The US National Cancer Institute and the American Lebanese Syrian Associated Charities.
To leverage baseline global longitudinal strain (GLS) and N-terminal-pro-B-type natriuretic peptide (NT-proBNP) to identify childhood cancer survivors with a normal left ventricular ejection fraction ...(LVEF) at highest risk of future treatment-related cardiomyopathy.
St Jude Lifetime Cohort participants ≥5 years from diagnosis, at increased risk for cardiomyopathy per the International Guideline Harmonization Group (IGHG), with an LVEF ≥50% on baseline echocardiography (n = 1,483) underwent measurement of GLS (n = 1,483) and NT-proBNP (n = 1,052; 71%). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs for postbaseline cardiomyopathy (modified Common Terminology Criteria for Adverse Events ≥grade 2) incidence in association with echocardiogram-based GLS (≥-18) and/or NT-proBNP (>age-sex-specific 97.5th percentiles). Prediction performance was assessed using AUC in models with and without GLS and NT-proBNP and compared using DeLong's test for IGHG moderate- and high-risk individuals treated with anthracyclines.
Among survivors (median age, 37.6; range, 10.2-70.4 years), 162 (11.1%) developed ≥grade 2 cardiomyopathy 5.1 (0.7-10.0) years from baseline assessment. The 5-year cumulative incidence of cardiomyopathy for survivors with and without abnormal GLS was, respectively, 7.3% (95% CI, 4.7 to 9.9) versus 4.4% (95% CI, 3.0 to 5.7) and abnormal NT-proBNP was 9.9% (95% CI, 5.8 to 14.1) versus 4.7% (95% CI, 3.2 to 6.2). Among survivors with a normal LVEF, abnormal baseline GLS and NT-proBNP identified anthracycline-exposed, IGHG-defined moderate-/high-risk survivors at a four-fold increased hazard of postbaseline cardiomyopathy (HR, 4.39 95% CI, 2.46 to 7.83;
< .001), increasing to a HR of 14.16 (95% CI, 6.45 to 31.08;
< .001) among survivors who received ≥250 mg/m
of anthracyclines. Six years after baseline, AUCs for individual risk prediction were 0.70 for models with and 0.63 for models without GLS and NT-proBNP (
= .022).
GLS and NT-proBNP should be considered for improved identification of survivors at high risk for future cardiomyopathy.
PDF
