Survivors of childhood cancer develop early and severe chronic health conditions (CHCs). A quantitative landscape of morbidity of survivors, however, has not been described. We aimed to describe the ...cumulative burden of curative cancer therapy in a clinically assessed ageing population of long-term survivors of childhood cancer.
The St Jude Lifetime Cohort Study (SJLIFE) retrospectively collected data on CHCs in all patients treated for childhood cancer at the St Jude Children's Research Hospital who survived 10 years or longer from initial diagnosis and were 18 years or older as of June 30, 2015. Age-matched and sex-frequency-matched community controls were used for comparison. 21 treatment exposure variables were included in the analysis, with data abstracted from medical records. 168 CHCs for all participants were graded for severity using a modified Common Terminology Criteria of Adverse Events. Multiple imputation with predictive mean matching was used for missing occurrences and grades of CHCs in the survivors who were not clinically evaluable. Mean cumulative count was used for descriptive cumulative burden analysis and marked-point-process regression was used for inferential cumulative burden analysis.
Of 5522 patients treated for childhood cancer at St Jude Children's Research Hospital who had complete records, survived 10 years or longer, and were 18 years or older at time of study, 3010 (54·5%) were alive, had enrolled, and had had prospective clinical assessment. 2512 (45·5%) of the 5522 patients were not clinically evaluable. The cumulative incidence of CHCs at age 50 years was 99·9% (95% CI 99·9–99·9) for grade 1–5 CHCs and 96·0% (95% CI 95·3–96·8%) for grade 3–5 CHCs. By age 50 years, a survivor had experienced, on average, 17·1 (95% CI 16·2–18·1) CHCs of any grade, of which 4·7 (4·6–4·9) were CHCs of grade 3–5. The cumulative burden in matched community controls of grade 1–5 CHCs was 9·2 (95% CI 7·9–10·6; p<0·0001 vs total study population) and of grade 3–5 CHCs was 2·3 (1·9–2·7, p<0·0001 vs total study population). Second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden. Notable heterogeneity in the distribution of CHC burden in survivors with differing primary cancer diagnoses was observed. The cumulative burden of grade 1–5 CHCs at age 50 years was highest in survivors of CNS malignancies (24·2 95% CI 20·9–27·5) and lowest in survivors of germ cell tumours (14·0 11·5–16·6). Multivariable analyses showed that older age at diagnosis, treatment era, and higher doses of brain and chest radiation are significantly associated with a greater cumulative burden and severity of CHCs.
The burden of CHCs in survivors of childhood cancer is substantial and highly variable. Our assessment of total cumulative burden in survivors of paediatric cancer, with detailed characterisation of long-term CHCs, provide data to better inform future clinical guidelines, research investigations, and health services planning for this vulnerable, medically complex population.
The US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities.
Adult survivors of childhood cancer are known to be at risk for treatment-related adverse health outcomes. A large population of survivors has not been evaluated using a comprehensive systematic ...clinical assessment to determine the prevalence of chronic health conditions.
To determine the prevalence of adverse health outcomes and the proportion associated with treatment-related exposures in a large cohort of adult survivors of childhood cancer.
Presence of health outcomes was ascertained using systematic exposure-based medical assessments among 1713 adult (median age, 32 range, 18-60 years) survivors of childhood cancer (median time from diagnosis, 25 range, 10-47 years) enrolled in the St Jude Lifetime Cohort Study since October 1, 2007, and undergoing follow-up through October 31, 2012.
Age-specific cumulative prevalence of adverse outcomes by organ system.
Using clinical criteria, the crude prevalence of adverse health outcomes was highest for pulmonary (abnormal pulmonary function, 65.2% 95% CI, 60.4%-69.8%), auditory (hearing loss, 62.1% 95% CI, 55.8%-68.2%), endocrine or reproductive (any endocrine condition, such as hypothalamic-pituitary axis disorders and male germ cell dysfunction, 62.0% 95% CI, 59.5%-64.6%), cardiac (any cardiac condition, such as heart valve disorders, 56.4% 95% CI, 53.5%-59.2%), and neurocognitive (neurocognitive impairment, 48.0% 95% CI, 44.9%-51.0%) function, whereas abnormalities involving hepatic (liver dysfunction, 13.0% 95% CI, 10.8%-15.3%), skeletal (osteoporosis, 9.6% 95% CI, 8.0%-11.5%), renal (kidney dysfunction, 5.0% 95% CI, 4.0%-6.3%), and hematopoietic (abnormal blood cell counts, 3.0% 95% CI, 2.1%-3.9%) function were less common. Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at age 50 years was 21.6% (95% CI, 19.3%-23.9%) for cardiomyopathy, 83.5% (95% CI, 80.2%-86.8%) for heart valve disorder, 81.3% (95% CI, 77.6%-85.0%) for pulmonary dysfunction, 76.8% (95% CI, 73.6%-80.0%) for pituitary dysfunction, 86.5% (95% CI, 82.3%-90.7%) for hearing loss, 31.9% (95% CI, 28.0%-35.8%) for primary ovarian failure, 31.1% (95% CI, 27.3%-34.9%) for Leydig cell failure, and 40.9% (95% CI, 32.0%-49.8%) for breast cancer. At age 45 years, the estimated cumulative prevalence of any chronic health condition was 95.5% (95% CI, 94.8%-98.6%) and 80.5% (95% CI, 73.0%-86.6%) for a serious/disabling or life-threatening chronic condition.
Among adult survivors of childhood cancer, the prevalence of adverse health outcomes was high, and a systematic risk-based medical assessment identified a substantial number of previously undiagnosed problems that are more prevalent in an older population. These findings underscore the importance of ongoing health monitoring for adults who survive childhood cancer.
Frailty and aging in cancer survivors Ness, Kirsten K.; Wogksch, Matthew D.
Translational research : the journal of laboratory and clinical medicine,
07/2020, Letnik:
221
Journal Article
Recenzirano
Odprti dostop
There are over 15 million survivors of cancer in the United States whose rates of frailty, an aging phenotype, range from just under 10% to over 80%. Frailty impacts not only disease survival but ...also long-term function and quality of life in children, adolescents, and in all adults diagnosed and/or treated for cancer. This review explains frailty as a construct and model of physiologic well-being. It also describes how frailty at diagnosis impacts cancer outcomes in adult populations and enumerates the prevalence of frailty in different populations of cancer survivors. Biological mechanisms responsible for aging and potentially for frailty among individuals with or who have been treated for cancer are discussed. Finally, promising pharmaceutical and lifestyle interventions designed to impact aging rather than a specific disease, tested in other populations, but likely applicable in cancer patients and survivors, are discussed.
Rates of obesity have increased significantly over the last three decades in the United States and globally. In addition to contributing to heart disease and diabetes, obesity is a major unrecognized ...risk factor for cancer. Obesity is associated with worsened prognosis after cancer diagnosis and also negatively affects the delivery of systemic therapy, contributes to morbidity of cancer treatment, and may raise the risk of second malignancies and comorbidities. Research shows that the time after a cancer diagnosis can serve as a teachable moment to motivate individuals to adopt risk-reducing behaviors. For this reason, the oncology care team--the providers with whom a patient has the closest relationships in the critical period after a cancer diagnosis--is in a unique position to help patients lose weight and make other healthy lifestyle changes. The American Society of Clinical Oncology is committed to reducing the impact of obesity on cancer and has established a multipronged initiative to accomplish this goal by 1) increasing education and awareness of the evidence linking obesity and cancer; 2) providing tools and resources to help oncology providers address obesity with their patients; 3) building and fostering a robust research agenda to better understand the pathophysiology of energy balance alterations, evaluate the impact of behavior change on cancer outcomes, and determine the best methods to help cancer survivors make effective and useful changes in lifestyle behaviors; and 4) advocating for policy and systems change to address societal factors contributing to obesity and improve access to weight management services for patients with cancer.
The improvement in survival of childhood cancer observed across the past 50 years has resulted in a growing acknowledgment that simply extending the lifespan of survivors is not enough. It is ...incumbent on both the cancer research and the clinical care communities to also improve the health span of survivors. It is well established that aging adult survivors of childhood cancer are at increased risk of chronic health conditions, relative to the general population. However, as the first generation of survivors age into their 50s and 60s, it has become increasingly evident that this population is also at risk of early onset of physiologic aging. Geriatric measures have uncovered evidence of reduced strength and speed and increased fatigue, all components of frailty, among survivors with a median age of 33 years, which is similar to adults older than 65 years of age in the general population. Furthermore, frailty in survivors independently increased the risk of morbidity and mortality. Although there has been a paucity of research investigating the underlying biologic mechanisms for advanced physiologic age in survivors, results from geriatric populations suggest five biologically plausible mechanisms that may be potentiated by exposure to cancer therapies: increased cellular senescence, reduced telomere length, epigenetic modifications, somatic mutations, and mitochondrial DNA infidelity. There is now a critical need for research to elucidate the biologic mechanisms of premature aging in survivors of childhood cancer. This research could pave the way for new frontiers in the prevention of these life-changing outcomes.
Summary Background The magnitude of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma is not known. Using medically ascertained data, we applied the ...cumulative burden metric to compare chronic cardiovascular health conditions in survivors of Hodgkin's lymphoma and general population controls. Methods For this study, participant data were obtained from two ongoing cohort studies at St Jude Children's Research Hospital: the St Jude Lifetime Cohort Study (SJLIFE) and the St Jude Long-term Follow-up Study (SJLTFU). SJLIFE is a cohort study initiated on April 27, 2007, to enable longitudinal clinical evaluation of health outcomes of survivors of childhood cancer treated or followed at St Jude Children's Research Hospital, and SJLTFU is an administrative system-based study initiated in 2000 to collect outcome and late toxicity data for all patients treated at the hospital for childhood cancer. The patient cohort for our study was defined as patients treated at St Jude Children's Research Hospital who reached 18 years of age and were at least 10 years post-diagnosis of pathologically confirmed primary Hodgkin's lymphoma. Outcomes in the Hodgkin's lymphoma survivors were compared with a sample of SJLIFE community control participants, aged 18 years or older at the time of assessment, frequency-matched based on strata defined by 5-year age blocks within each sex, who were selected irrespective of previous medical history. All SJLIFE participants underwent assessment for 22 chronic cardiovascular health conditions. Direct assessments, combined with retrospective clinical reviews, were used to assign severity to conditions using a modified Common Terminology Criteria of Adverse Events (CTCAE) version 4.03 grading schema. Occurrences and CTCAE grades of the conditions for eligible non-SJLIFE participants were accounted for by multiple imputation. The mean cumulative count (treating death as a competing risk) was used to estimate cumulative burden. Findings Of 670 survivors treated at St Jude Children's Research Hospital, who survived 10 years or longer and reached age 18 years, 348 were clinically assessed in the St Jude Lifetime Cohort Study (SJLIFE); 322 eligible participants did not participate in SJLIFE. Age and sex frequency-matched SJLIFE community controls (n=272) were used for comparison. At age 50 years, the cumulative incidence of survivors experiencing at least one grade 3–5 cardiovascular condition was 45·5% (95% CI 36·6–54·3), compared with 15·7% (7·0–24·4) in community controls. The survivor cohort at age 50 experienced a cumulative burden of 430·6 (95% CI 380·7–480·6) grade 1–5 and 100·8 (77·3–124·3) grade 3–5 cardiovascular conditions per 100 survivors; these numbers were appreciably higher than those in the control cohort (227·4 192·7–267·5 grade 1–5 conditions and 17·0 8·4–27·5 grade 3–5 conditions per 100 individuals). Myocardial infarction and structural heart defects were the major contributors to the excess grade 3–5 cumulative burden in survivors. High cardiac radiation dose (≥35 Gy) was associated with an increased proportion of grade 3–5 cardiovascular burden, whereas increased anthracyline dose was not. Interpretation The true effect of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma is reflected in the cumulative burden. Survivors aged 50 years will experience more than two times the number of chronic cardiovascular health conditions and nearly five times the number of more severe (grade 3–5) cardiovascular conditions compared with community controls and, on average, have one severe, life-threatening, or fatal cardiovascular condition. The cumulative burden metric provides a more comprehensive approach for assessing overall morbidity compared with currently used cumulative incidence based analytic methodologies, and will assist clinical researchers when designing future trials and refining general practice screening guidelines. Funding US National Cancer Institute, St Baldrick's Foundation, and American Lebanese Syrian Associated Charities.
Exercise intolerance, associated with heart failure and death in general populations, is not well studied in survivors of childhood cancer. We examined prevalence of exercise intolerance in survivors ...exposed or not to cardiotoxic therapy, and associations among organ system function, exercise intolerance, and mortality.
Participants consisted of 1,041 people who had survived cancer ≥ 10 years (and had or did not have exposure to anthracyclines and/or chest-directed radiation) and 285 control subjects. Exercise intolerance was defined as peak oxygen uptake < 85% predicted from maximal cardiopulmonary exercise testing; organ functions were ascertained with imaging or clinical testing. Multivariable regression of the data was performed to compare exercise capacity between survivors exposed or unexposed to cardiotoxic therapy and control subjects, and to evaluate associations between treatment and organ function, and organ function and exercise intolerance. Propensity score methods in time-to-event analyses evaluated associations between exercise intolerance and mortality.
Survivors (mean age ± standard deviation SD, 35.6 ± 8.8 years) had lower mean (± SD) peak oxygen uptake (exposed: 25.74 ± 8.36 mL/kg/min; unexposed: 26.82 ± 8.36 mL/kg/min) than did control subjects (32.69 ± 7.75 mL/kg/min;
for all < .001). Exercise intolerance was present in 63.8% (95% CI, 62.0% to 65.8%) of exposed survivors, 55.7% (95% CI, 53.2% to 58.2%) of unexposed survivors, and 26.3% (95% CI, 24.0% to 28.3%) of control subjects, and was associated with mortality (hazard ratio, 3.9; 95% CI, 1.09 to 14.14). Global longitudinal strain (odds ratio OR, 1.71; 95% CI, 1.11 to 2.63), chronotropic incompetence (OR, 3.58; 95% CI, 1.75 to 7.31); forced expiratory volume in 1 second < 80% (OR, 2.59; 95% CI, 1.65 to 4.09), and 1 SD decrease in quadriceps strength (OR, 1.49; 95% CI, 1.23 to 1.82) were associated with exercise intolerance. Ejection fraction < 53% was not associated with exercise intolerance.
Exercise intolerance is prevalent among childhood cancer survivors and associated with all-cause mortality. Treatment-related cardiac (detected by global longitudinal strain), autonomic, pulmonary, and muscular impairments increased risk. Survivors with impairments may require referral to trained specialists to learn to accommodate specific deficits when engaging in exercise.
To determine rates, patterns, and predictors of neurocognitive impairment in adults decades after treatment for childhood acute lymphoblastic leukemia (ALL).
Survivors of childhood ALL treated at St ...Jude Children's Research Hospital who were still alive at 10 or more years after diagnosis and were age ≥ 18 years were recruited for neurocognitive testing. In all, 1,014 survivors were eligible, 738 (72.8%) agreed to participate, and 567 (76.8%) of these were evaluated. Mean age was 33 years; mean time since diagnosis was 26 years. Medical record abstraction was performed for data on doses of cranial radiation therapy (CRT) and cumulative chemotherapy. Multivariable modeling was conducted and glmulti package was used to select the best model with minimum Akaike information criterion.
Impairment rates across neurocognitive domains ranged from 28.6% to 58.9%, and those treated with chemotherapy only demonstrated increased impairment in all domains (all P values < .006). In survivors who received no CRT, dexamethasone was associated with impaired attention (relative risk RR, 2.12; 95% CI, 1.11 to 4.03) and executive function (RR, 2.42; 95% CI, 1.20 to 4.91). The impact of CRT was dependent on young age at diagnosis for intelligence, academic, and memory functions. Risk for executive function problems increased with survival time in a CRT dose-dependent fashion. In all survivors, self-reported behavior problems increased by 5% (RR, 1.05; 95% CI, 1.01 to 1.09) with each year from diagnosis. Impairment was associated with reduced educational attainment and unemployment.
This study demonstrates persistent and significant neurocognitive impairment in adult survivors of childhood ALL and warrants ongoing monitoring of brain health to facilitate successful adult development and to detect early onset of decline as survivors mature.
Abstract
Context:
Long-term follow-up data on premature ovarian insufficiency (POI) in childhood cancer survivors are limited.
Objective:
To describe the prevalence of POI, its risk factors, and ...associated long-term adverse health outcomes.
Design:
Cross-sectional.
Setting:
The St. Jude Lifetime Cohort Study, an established cohort in a tertiary care center.
Patients:
Nine hundred twenty-one participants (median age, 31.7 years) were evaluated at a median of 24.0 years after cancer diagnosis.
Main Outcome Measure:
POI was defined by persistent amenorrhea combined with a follicle-stimulating hormone level >30 IU/L before age 40. Multivariable Cox regression was used to study associations between demographic or treatment-related risk factors and POI. Multivariable logistic regression was used to study associations between POI and markers for cardiovascular disease, bone mineral density (BMD), and frailty. Exposure to alkylating agents was quantified using the validated cyclophosphamide equivalent dose (CED).
Results:
The prevalence of POI was 10.9%. Independent risk factors for POI included ovarian radiotherapy at any dose and CED ≥8000 mg/m2. Patients with a body mass index ≥30 kg/m2 at the time of the St. Jude Lifetime Cohort assessment were less likely to have a diagnosis of POI. Low BMD and frailty were independently associated with POI.
Conclusion:
High-dose alkylating agents and ovarian radiotherapy at any dose are associated with POI. Patients at the highest risk should be offered fertility preservation whenever feasible. POI contributes to poor general health outcomes in childhood cancer survivors; further studies are needed to investigate the role of sex hormone replacement in improving such outcomes.
We report on the prevalence, risk factors, and consequences on general health of premature ovarian insufficiency in a cohort of 921 long-term survivors of childhood cancers.
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