Late effects in long-term survivors of ALL in childhood: experiences from the SPOG late effects study

With the use of more intensive regimens including prophylactic CNS treatment, the prognosis of children with ALL has dramatically improved over the last three decades. The aim of this cross-sectional, nationwide study was to comprehensively assess long-term toxicity in ALL survivors, with special attention given to neuropsychological morbidity, and to look for possible differences in cognitive outcome between children having received prophylactic cranial irradiation and those not having received it. Between 1994 and 1996, long-term survivors of ALL were assessed in a multi-center setting according to a standardized protocol which included, besides usual clinical and laboratory investigations, a comprehensive endocrine work-up. Additionally, children having received anthracyclines were checked for possible late cardio-toxicity with echocardiography and ECG. Intellectual performance was evaluated with standardized neuropsychological tests (age-adapted versions of the Wechsler test). One-hundred and fifty patients were eligible for the study. The median age at diagnosis was 5 years and at evaluation 16 years, for a median follow-up of 10 years. Thirty-five patients had cranial irradiation as part of the prophylactic CNS treatment. One-hundred and forty (93%) of the 150 eligible patients were completely evaluated in terms of global long-term toxicity: 117 (83%) long-term survivors had no (n = 61) or only minimal (n = 56) late toxicity; 19 (14%) suffered from moderate impairments; 4 (3%) showed severe somatic or neuropsychological sequelae. Intellectual performance could be assessed in 147 (98%) of the 150 eligible patients. The mean global, verbal and non-verbal IQs (103, 105 and 101 respectively) of the ALL survivors as a group were comparable with those found in the general population. The results of the comparison between children having and those not having received prophylactic cranial irradiation showed: 1) significantly higher scores in chemotherapy-only treated patients, both for the global and the verbal performances; 2) significantly poorer results in specific items of the Wechsler test (short-term verbal memory, arithmetics, concentration/speed of processing) in irradiated children. These findings which show the deleterious role of cranial irradiation correlate well with many other reports found in the literature. However, they could have been influenced by the significantly longer time interval observed between therapy and evaluation in our irradiated patients. Prospective studies are needed to further characterize the potential neuropsychological hazards of chemotherapy and their evolution over time.     

Impact of breast cancer survivorship on quality of life in older women

Quality of life (QOL) is an important outcome for cancer survivors; but although age is a major risk factor, most breast cancer survivorship studies are conducted with younger women. The objective of our study was to compare QOL in a sample of older breast cancer survivors to a sample of older women who were never diagnosed with breast cancer. A sample of 127 older breast cancer survivors as identified by a cancer registry was compared to a demographically equated sample of 87 older women participating in an epidemiological study. Both groups completed a questionnaire and participated in an interview to measure QOL. The older breast cancer survivors scored worse in the Medical Outcomes Study-Short Form, a measure of health-related QOL. Survivors reported no more depressive symptoms or anxious mood than the comparison group, but scored lower in measures of positive psychosocial well-being, including life satisfaction, mastery, and spiritual well-being, and reported more depressed mood and days affected by fatigue. Older breast cancer survivors show multiple indications of decrements in their health-related quality of life, and lower psychosocial well-being than the comparison group. These decrements may represent deficits in reserve capacity that predispose older cancer survivors to functional disability but may not be readily detected in typical clinical evaluations given the multiple impairments common in geriatric populations. Results suggest a need for greater attention to promoting functioning and psychological well-being among older cancer survivors, even when they may not have obvious cancer-related medical complications.     

Twenty-five-year follow-up among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study

Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for late effects of cancer therapy. Five-year ALL survivors (< 21 years at diagnosis; n = 5760 eligible, 4151 participants), diagnosed from 1970 to 1986 were compared with the general population and a sibling cohort (n = 3899). Cumulative mortality of 5760 5-year survivors was 13% at 25 years from diagnosis. Recurrent ALL (n = 483) and second neoplasms (SNs; n = 89) were the major causes of death. Among 185 survivors, 199 SNs occurred, 53% in the CNS. Survivors reported more multiple chronic medical conditions (CMCs; odds ratio [OR], 2.8; 95% CI, 2.4-3.2) and severe or life-threatening CMCs (OR, 3.6; 95% CI, 3.0-4.5) than siblings. Cumulative incidence of severe CMCs, including death, 25 years from diagnosis was 21.3% (95% CI, 18.2-24.4; 23.3% [95% CI, 19.4-27.2] and 13.4% [95% CI, 8.4-18.4] for irradiated and nonirradiated survivors, respectively). Survivors reported more adverse general and mental health, functional impairment, and activity limitations compared with siblings (P < .001). Rates of marriage, college graduation, employment, and health insurance were all lower compared with sibling controls (P < .001). Long-term survivors of childhood ALL exhibit excess mortality and morbidity. Survivors who received radiation therapy as part of their treatment or had a leukemia relapse are at greatest risk for adverse outcomes.     

Adverse effects of treatment in childhood acute lymphoblastic leukemia: general overview and implications for long-term cardiac health

Survival of childhood acute lymphoblastic leukemia (ALL) is one of the greatest medical success stories of the last four decades. Unfortunately, childhood ALL survivors experience medical late effects that increase their risk of morbidity and premature death, often due to heart and vascular disease. Research has helped elucidate the mechanisms and trajectory of direct damage to the heart from treatment exposure, particularly to anthracyclines, and has also contributed knowledge on the influences of related chronic conditions, such as obesity and insulin resistance on heart health in these survivors. This article summarizes the key issues associated with early morbidity and mortality from cardiac-related disease in childhood ALL survivors and suggests directions for interventions to improve long-term outcomes.     

Late effects in survivors of childhood acute lymphoblastic leukemia: a study from Thai Pediatric Oncology Group

Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk of long-term late effects. Therefore, systematic screenings of the late complications are essential. The objective of this study was to determine the prevalence of late effects of Thai children and adolescents after completion of ALL therapy. We performed a cross-sectional study for evaluation of the late effects in ALL survivors who came for follow-up at 10 pediatric oncology centers in Thailand. We evaluated the treatment-related late complications of children and adolescents who had finished ALL treatment for at least 2 years. Demographic data, treatment modalities, and late effects were recorded and analyzed. There were 258 survivors with a median age of 12.2 years (range 3.6–23.3 years). The median follow-up time was 7.2 years (range 2–17.5 years). Forty-seven percent (122 cases) suffered from at least one late effect. Overweight/obesity was the most common late effect. Radiation of central nervous system was a significant risk factor for overweight/obesity (OR 1.97, 95% CI 1.02–3.81) and educational problems (OR 4.3, 95% CI 1.32–14.02). Our data have demonstrated a significant prevalence of late effects after childhood ALL therapy. A long-term follow-up program for survivors of childhood cancer is therefore needed in our country.     

Molecular markers in ALL: Clinical implications

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and remains a main cause of death in children despite recent improvements in cure rates. In the past decade, development of massively parallel sequencing has enabled large scale genome profiling studies of ALL, which not only led to identification of new subtypes in both B-cell precursor ALL (BCP-ALL) and T-cell ALL (T-ALL), but has also identified potential new therapeutic approaches to target vulnerabilities of many subtypes. Several of these approaches have been validated in preclinical models and are now being formally evaluated in prospective clinical trials. In this review, we provide an overview of the recent advances in our knowledge of genomic bases of BCP-ALL, T-ALL, and relapsed ALL, and discuss their clinical implications.     

MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, whereas acute myeloid leukemia (AML) is the most common acute leukemia in adults. In general, ALL has a better prognosis than AML. To understand the distinct mechanisms in leukemogenesis between ALL and AML and to identify markers for diagnosis and treatment, we performed a large-scale genome-wide microRNA (miRNA, miR) expression profiling assay and identified 27 miRNAs that are differentially expressed between ALL and AML. Among them, miR-128a and -128b are significantly overexpressed, whereas let-7b and miR-223 are significantly down-regulated in ALL compared with AML. They are the most discriminatory miRNAs between ALL and AML. Using the expression signatures of a minimum of two of these miRNAs resulted in an accuracy rate of >95% in the diagnosis of ALL and AML. The differential expression patterns of these four miRNAs were validated further through large-scale real-time PCR on 98 acute leukemia samples covering most of the common cytogenetic subtypes, along with 10 normal control samples. Furthermore, we found that overexpression of miR-128 in ALL was at least partly associated with promoter hypomethylation and not with an amplification of its genomic locus. Taken together, we showed that expression signatures of as few as two miRNAs could accurately discriminate ALL from AML, and that epigenetic regulation might play an important role in the regulation of expression of miRNAs in acute leukemias.     

C-reactive protein as a biomarker for urological cancers

Systemic inflammation has been linked with the progression of cancer, and, in patients with urological cancers, the presence of a systemic inflammatory response is thought to be indicative of poor prognosis. C-reactive protein (CRP) is an acute-phase reactant, the levels of which can be objectively measured using standardized reliable assays, and a useful marker of systemic inflammation. CRP levels have been shown to predict survival in patients with urological cancers, including renal cell carcinoma, upper urinary tract and bladder cancers, and prostate cancer, and the incorporation of CRP into prognostic models for urological cancers improves the models' predictive accuracy. Furthermore, the kinetics of CRP release and the analysis of dynamic changes in CRP concentrations over time, could predict tumor aggressiveness and potential treatment efficacy. For instance, in long-term survivors of testicular cancer, CRP is associated with the risk of late complications, such as cardiovascular disease, and with the development of second non-germ-cell cancer. CRP could, therefore, be an important biomarker for urological cancers.     

Growth hormone deficiency predicts cardiovascular risk in young adults treated for acute lymphoblastic leukemia in childhood

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and until recently prophylactic cranial radiotherapy (CRT) was important for achieving long-term survival. Hypothalamic-pituitary hormone insufficiency is a well-recognized consequence of CRT for childhood cancer. Another problem is increased cardiovascular risk, which has been shown in long-term survivors of other childhood cancers. In the only previously reported study on cardiovascular risk after childhood ALL, obesity and dyslipidemia were recorded in a small subgroup treated with CRT, compared with patients treated with chemotherapy. The mechanisms behind the increase in cardiovascular risk in survivors of childhood cancer are not clarified.The aim of the present study was to elucidate mechanisms of increased cardiovascular risk in former childhood ALL patients. A group of 44 ALL survivors (23 males, median age 25 yr, range 19-32 yr at the time of study) treated with CRT (median 24 Gy, 18-30 Gy) at a median age of 5 yr (1-18 yr) and chemotherapy were investigated for prevalence of GH deficiency and cardiovascular risk factors. Comparison was made with controls randomly selected from the general population and individually matched for sex, age, smoking habits, and residence. All patients and controls underwent a GHRH-arginine test, and patients with a peak GH 3.9 microg/liter or greater were further investigated with an additional insulin tolerance test.Significantly higher plasma levels of insulin (P = 0.002), blood glucose (P = 0.01), and serum levels of low-density lipoprotein cholesterol, apolipoprotein (Apo) B, triglycerides, fibrinogen, and leptin (all P 相似文献   

K?rperliche Aktivit?t und Tumorkrankheiten

Physical activity is an important health measure for many diseases but in the past its role in cancer control has been understudied and underappreciated. This chapter updates a review of physical activity and cancer risk. Overall, the research to date suggests that physical activity reduces the risk of developing some forms of cancer, helps cancer survivors cope with and recover from treatment, improves the long-term health of cancer survivors and possibly even reduces the risk of recurrence and extends survival in some cancer survivor groups. Much research remains to be done in this field but the compelling data produced so far suggests that physical activity has an important effect on the development of cancer and precursor stages.     

Exercise issues in older cancer survivors

Older cancer survivors experience the combined deleterious effects associated with aging and a cancer diagnosis. The purpose of the present paper is to review the potential role of physical exercise in attenuating the effects of cancer and its treatments in older cancer survivors. Noting the limited direct research on exercise in older cancer survivors, we review the literature on: (a) older adults in general; and (b) cancer survivors in general. We conclude that although there is limited direct evidence on the benefits of exercise in older cancer survivors, there is compelling evidence of the benefits of exercise in cancer survivors in general and other older populations. We also conclude that exercise adherence will be a significant challenge in this population. Based on this evidence, we tentatively recommend exercise to older cancer survivors using the American College of Sports Medicine's [Med Sci Sports Exerc 30 (6) (1998) 992] guidelines for older adults in general. Finally, we offer future research directions that will provide important evidence needed to guide clinical decisions about exercise in older cancer survivors.     

Non‐irradiated female survivors of childhood acute lymphoblastic leukaemia are at risk of long‐term increases in weight and body mass index

We report long‐term, including final height, auxological data from our retrospective study of non‐irradiated survivors of childhood acute lymphoblastic leukaemia (ALL). Body mass index (BMI) standard deviation score (SDS) increases in females, due to increased weight‐SDS, persisted to final height, with probable adverse long‐term health outcomes. In contrast, males demonstrated increased BMI‐SDS in follow‐up, due to reduced height‐SDS, not increased weight‐SDS, but such changes had resolved by final height. Childhood ALL survivors, particularly females, are therefore at potential increased risk of developing the metabolic syndrome during follow‐up. We recommend that strategies to minimize weight gain should be implemented during ALL treatment.     

Bone mineral density in childhood survivors of acute lymphoblastic leukemia treated without cranial irradiation

Adult survivors of childhood acute lymphoblastic leukemia (ALL) whose treatment included cranial irradiation (XRT) have reduced bone mineral density (BMD). Fifty-three survivors of ALL (aged 6-17 yr; 22 males and 31 females), who had completed their treatment without XRT, at least 1 yr previously, and 187 (5-19 yr; 86 males and 101 females) healthy controls were examined with dual energy x-ray absorptiometry of the total body and L1-L4 vertebrae and peripheral quantitative computer tomography at the distal and midradial sites. The total body and lumbar spine BMDs did not differ between the ALL survivors and controls. Distal radial trabecular BMD (difference, -0.080 mg/cm(3); 95% confidence interval, -0.139 to -0.020; P = 0.009), but not total BMD (difference, -0.006 mg/cm(3); confidence interval, -0.051 to 0.039; P = 0.80), was lower in ALL survivors compared with controls. At the midradial site, both endosteal (11% larger; P = 0.0001) and periosteal (4% larger; P = 0.001) circumferences were greater, and cortical thickness was thinner by 6% (P = 0.006) in the ALL subjects, leading to an increase in the axial moment of inertia in the ALL subjects (difference, 13%; P = 0.008). In conclusion, BMD, except at the radius, is normal in childhood survivors of ALL treated without XRT. At the midradial site, we speculate that ALL or its treatment resulted in endosteal bone loss and cortical bone thinning, but the axial moment of inertia and, hence, strength was maintained as a result of bone gain at the periosteal surface.     

Abdominal obesity, liver fat, and muscle composition in survivors of childhood acute lymphoblastic leukemia

CONTEXT: Survivors of childhood acute lymphoblastic leukemia (ALL) become obese, and are at increased risk for morbidity and mortality post therapy. OBJECTIVE: We determined the association of cranial radiotherapy (CRT) and/or sex with levels of total, regional, and ectopic fat storage, metabolic risk, IGF-I, and leptin in adult ALL survivors. DESIGN, SETTING, PATIENTS: A cross-sectional analysis of 52 male (15 CRT treated) and 62 female (24 CRT treated) young adult ALL survivors was conducted. MAIN OUTCOMES: We assessed levels of visceral fat, sc abdominal and thigh fat, and liver and muscle fat using computed tomography, total fat and lean body mass using dual-energy x-ray absorptiometry, and IGF-I and leptin levels by radioimmunoassay. RESULTS: Controlled for age and race, ALL survivors treated with CRT had higher levels of abdominal and visceral fat, body fat percentage, metabolic risk (insulin resistance and dyslipidemia), and leptin but lower lean mass and IGF-I levels than non-CRT survivors (P 0.1). CONCLUSION: Among young adult ALL survivors, CRT is a risk factor for elevated total, abdominal, and visceral adiposity, a reduced fat-free mass, elevated metabolic risk, and altered IGF-I and leptin levels.     

Adult and childhood acute lymphocytic leukemia: Are they different diseases?

Age has long been recognized as an important factor in predicting response to treatment for acute lymphocytic leukemia (ALL). Specifically, the results of treatment of childhood ALL have been far superior to the treatment of what appears to be the same disease in adults. However, from an analysis of the clinical and biological prognostic factors known to be predictive in childhood ALL, there is a striking difference in their distribution in adults with ALL. It appears that there is a special form of ALL seen in children of some populations with a peak incidence of three to seven years. This treatment responsive leukemia appears to be different clinically, biologically, and epidemiologically from adult ALL. © 1993 Wiley-Liss, Inc.     

Cardiomyopathy Associated With Cancer Therapy

Chemotherapy-associated cardiomyopathy is a well known cardiotoxicity of contemporary cancer treatment and a cause of increasing concern for both cardiologists and oncologists. As cancer outcomes improve, cardiovascular disease has become a leading cause of morbidity and mortality among cancer survivors. Asymptomatic or symptomatic left ventricular systolic dysfunction in the setting of cardiotoxic chemotherapy is an important entity to recognize. Early diagnosis of cardiac injury through the use of novel blood-based biomarkers or noninvasive imaging modalities may allow for the initiation of cardioprotective medications or modification of chemotherapy regimen to minimize or prevent further damage. Several clinical trials are currently underway to determine the efficacy of cardioprotective medications for the prevention of chemotherapy-associated cardiomyopathy. Implementing a strategy that includes both early detection and prevention of cardiotoxicity will likely have a significant impact on the overall prognosis of cancer survivors. Continued coordination of care between cardiologists and oncologists remains critical to maximizing the oncologic benefit of cancer therapy while minimizing any early or late cardiovascular effects.     

Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.     

Radiation Therapy and Cardiovascular Disease Risk in Breast Cancer

The cardiovascular disease risk among the breast cancer population is becoming increasingly important as the population of long-term survivors continues to rise. Radiation therapy decreases local reoccurrence and improves overall survival. These benefits however are not met without challenges including the potential for an increased risk of developing cardiovascular disease. Early clinical trials demonstrate that cardiovascular mortality is increased following radiation therapy compared to those treated without radiation therapy. Cardiovascular disease morbidity is also associated with radiation therapy for women with breast cancer. Among those who are irradiated, potential risk factors including age, surgery type, left-sided disease, dose, and previous cardiovascular disease may increase the risk of developing fatal cardiovascular disease. Newer clinical trials are showing promising results, with a decline in cardiovascular disease risk among those treated with radiation therapy; however, longer-term follow up is needed to confirm these findings.     

Long-term survivorship in lung cancer: a review

While outcome research in lung cancer has focused mainly on short-term survival and quality of life (QoL), information on long-term (ie, > 5 years postdiagnosis) lung cancer survivorship remains limited. This review addresses the epidemiologic significance of long-term lung cancer (LTLC) survivors, summarizes the current knowledge on their health and QoL, and suggests areas for further research in LTLC survivorship. Based on a small body of literature, lung cancer survivors do not experience the same quantity and QoL as their age-matched peers or as survivors of other cancers. Survival among 5-year survivors of lung cancer relative to the general US population with the same demographic characteristics is approximately 60%, and lung cancer survivors score lowest in health utility among long-term survivors of other cancers. Approximately one-quarter of long-term lung cancer (LTLC) survivors were significantly restricted in physical ability or reported significant depressive symptoms. There is a need to identify and intervene with subgroups of survivors who are at an elevated risk of premature death and diminished QoL. Lung cancer-specific survival alone does not reflect the overall illness burden in LTLC survivors. Patient care in lung cancer survivors should be continuous and comprehensive in considering multiple causes of health deterioration. Multidisciplinary research in epidemiologic, clinical, and basic science approaches is warranted to further our knowledge base for optimal long-term management and to develop the necessary intervention strategies among LTLC survivors.     

Changes in body composition after childhood cancer treatment: impact on future health status--a review

PURPOSE: To describe data on changes in body composition in childhood cancer survivors. Underlying mechanisms in development of obesity are addressed, in order to discuss intervention strategies. METHODS: A systematic literature search was undertaken with a number of search terms. RESULTS: Female survivors of ALL and brain tumours, especially if treated with cranial irradiation, showed a higher prevalence of obesity compared with the general population, while survivors of other malignancies had a higher prevalence of underweight. Influences of corticosteroid treatment and cytostatics on body composition are uncertain. Diminished physical activity, early adiposity rebound (<5 years of age) and/or hypothalamic involvement of tumour or treatment, and subsequent growth hormone deficiency, may play a role in the development of obesity in childhood cancer survivors. CONCLUSION: Longitudinal prospective studies in more extensive cohorts are necessary to estimate actual prevalence and facilitate the unravelling of the underlying mechanisms in change of body composition.