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The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Criança , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Sedação Consciente/métodos , Masculino , FemininoRESUMO
Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), female breast cancer (OR = 1.42, 95% CI = 1.27-1.58), thyroid cancer (OR = 1.48, 95% CI = 1.31-1.67), squamous cell carcinoma (OR = 1.20, 95% CI = 1.00-1.44) and melanoma (OR = 1.60, 95% CI = 1.31-1.96); however, the association for colorectal cancer was not significant (OR = 1.19, 95% CI = 0.94-1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk.
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Neoplasias da Mama , Sobreviventes de Câncer , Carcinoma Basocelular , Neoplasias , Neoplasias Cutâneas , Neoplasias da Glândula Tireoide , Humanos , Criança , Feminino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias/radioterapia , Estratificação de Risco Genético , Estudo de Associação Genômica Ampla , Fatores de Risco , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genéticaRESUMO
BACKGROUND: Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences has not been well described. METHODS: Late mortality, subsequent malignant neoplasms (SMNs), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year Childhood Cancer Survivor Study (CCSS) survivors of neuroblastoma diagnosed 1987-1999. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n = 425]; intermediate [n = 252]; high [n = 245]). Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) of SMNs were compared with matched population controls. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals for CHC compared with 1029 CCSS siblings. RESULTS: Among survivors (49.8% male; median age = 21 years, range = 7-42; median follow-up = 19.3 years, range = 5-29.9), 80% with low-risk disease were treated with surgery alone, whereas 79.1% with high-risk disease received surgery, radiation, chemotherapy ± autologous stem cell transplant (ASCT). All-cause mortality was elevated across risk groups (SMRhigh = 27.7 [21.4-35.8]; SMRintermediate = 3.3 [1.7-6.5]; SMRlow = 2.8 [1.7-4.8]). SMN risk was increased among high- and intermediate-risk survivors (SIRhigh = 28.0 [18.5-42.3]; SIRintermediate = 3.7 [1.2-11.3]) but did not differ from the US population for survivors of low-risk disease. Compared with siblings, survivors had an increased risk of grade 3-5 CHCs, particularly among those with high-risk disease (HRhigh = 16.1 [11.2-23.2]; HRintermediate = 6.3 [3.8-10.5]; HRlow = 1.8 [1.1-3.1]). CONCLUSION: Survivors of high-risk disease treated in the early days of risk stratification carry a markedly elevated burden of late recurrence, SMN, and organ-related multimorbidity, whereas survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes.
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Sobreviventes de Câncer , Neuroblastoma , Humanos , Neuroblastoma/mortalidade , Neuroblastoma/terapia , Masculino , Feminino , Sobreviventes de Câncer/estatística & dados numéricos , Criança , Adolescente , Adulto , Adulto Jovem , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/mortalidade , Fatores de Risco , Estados Unidos/epidemiologia , Modelos de Riscos Proporcionais , Incidência , Pré-EscolarRESUMO
Pediatric glioma therapy has evolved to delay or eliminate radiation for low-grade tumors. This study examined these temporal changes in therapy with long-term outcomes in adult survivors of childhood glioma. Among 2,501 5-year survivors of glioma in the Childhood Cancer Survivor Study diagnosed 1970-1999, exposure to radiation decreased over time. Survivors from more recent eras were at lower risk of late mortality (≥5 years from diagnosis), severe/disabling/life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs). Adjusting for treatment exposure (surgery only, chemotherapy, or any cranial radiation) attenuated this risk (for example, CHCs (1990s versus 1970s), relative risk (95% confidence interval), 0.63 (0.49-0.80) without adjustment versus 0.93 (0.72-1.20) with adjustment). Compared to surgery alone, radiation was associated with greater than four times the risk of late mortality, CHCs and SNs. Evolving therapy, particularly avoidance of cranial radiation, has improved late outcomes for childhood glioma survivors without increased risk for late recurrence.
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Neoplasias Encefálicas , Sobreviventes de Câncer , Glioma , Humanos , Glioma/mortalidade , Glioma/terapia , Glioma/radioterapia , Sobreviventes de Câncer/estatística & dados numéricos , Masculino , Feminino , Adulto , Criança , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/radioterapia , Adolescente , Adulto Jovem , Pré-Escolar , Morbidade , Fatores de Tempo , Pessoa de Meia-IdadeRESUMO
As childhood cancer treatments have improved to include new and innovative agents, the need for more advanced monitoring of their long-term effects and related research has increased. This has resulted in a need for evidence-based research methodologies for the longitudinal care of childhood cancer patients treated with targeted agents and immunotherapies. The rationale for this pilot study was to determine the feasibility and acceptability of a data capture methodology for pediatric, adolescent, and young adult cancer patients treated with targeted agents and immunotherapy as there is little research to inform this delivery of care. Data were collected from thirty-two patients and two providers for descriptive statistics and thematic analyses. Feasibility was characterized by expected participant attrition. Key drivers of acceptability were (1) providers' language and clarity of communication and (2) convenient participation requirements. Long-term follow-up research practices developed with input from key stakeholders, including patients, caregivers, and providers, can lead to acceptable and feasible research protocols that optimize successful participant recruitment. These evidence-based research practices can result in high participant satisfaction and can be implemented as program development initiatives across centers caring for childhood cancer survivors.
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Atenção à Saúde , Neoplasias , Adolescente , Adulto Jovem , Humanos , Criança , Estudos de Viabilidade , Projetos Piloto , Neoplasias/tratamento farmacológico , ImunoterapiaRESUMO
BACKGROUND: Sleep problems following childhood cancer treatment may persist into adulthood, exacerbating cancer-related late effects and putting survivors at risk for poor physical and psychosocial functioning. This study examines sleep in long-term survivors and their siblings to identify risk factors and disease correlates. METHODS: Childhood cancer survivors (≥5 years from diagnosis; n = 12â340; 51.5% female; mean [SD] age = 39.4 [9.6] years) and siblings (n = 2395; 57.1% female; age = 44.6 [10.5] years) participating in the Childhood Cancer Survivor Study completed the Pittsburgh Sleep Quality Index (PSQI). Multivariable Poisson-error generalized estimating equation compared prevalence of binary sleep outcomes between survivors and siblings and evaluated cancer history and chronic health conditions (CHC) for associations with sleep outcomes, adjusting for age (at diagnosis and current), sex, race/ethnicity, and body mass index. RESULTS: Survivors were more likely to report clinically elevated composite PSQI scores (>5; 45.1% vs 40.0%, adjusted prevalence ratio [PR] = 1.20, 95% CI = 1.13 to 1.27), symptoms of insomnia (38.8% vs 32.0%, PR = 1.26, 95% CI = 1.18 to 1.35), snoring (18.0% vs 17.4%, PR = 1.11, 95% CI = 1.01 to 1.23), and sleep medication use (13.2% vs 11.5%, PR = 1.28, 95% CI = 1.12 to 1.45) compared with siblings. Within cancer survivors, PSQI scores were similar across diagnoses. Anthracycline exposure (PR = 1.13, 95% CI = 1.03 to 1.25), abdominal radiation (PR = 1.16, 95% CI = 1.04 to 1.29), and increasing CHC burden were associated with elevated PSQI scores (PRs = 1.21-1.48). CONCLUSIONS: Among survivors, sleep problems were more closely related to CHC than diagnosis or treatment history, although longitudinal research is needed to determine the direction of this association. Frequent sleep-promoting medication use suggests interest in managing sleep problems; behavioral sleep intervention is advised for long-term management.
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Sobreviventes de Câncer , Neoplasias , Transtornos do Sono-Vigília , Humanos , Criança , Feminino , Adulto , Masculino , Neoplasias/terapia , Qualidade de Vida/psicologia , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/psicologia , Doença Crônica , SonoRESUMO
Background Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods and Results We designed a matched case-control study (Children's Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified "hepatic fibrosis" and "iron homeostasis" pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (LDHA) and cluster of differentiation 36 (CD36) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (IL1R1, IL1R2), and matrix metalloproteinase 8, 9 (MMP8, MMP9) appeared in multiple canonical pathways. LDHA-knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. Conclusions We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of LDHA and CD36 genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors IL1R1 and IL1R2 and matrix metalloproteinases, MMP8 and MMP9 indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.
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Sobreviventes de Câncer , Cardiomiopatias , Neoplasias , Humanos , Criança , Metaloproteinase 8 da Matriz/genética , Metaloproteinase 8 da Matriz/uso terapêutico , Metaloproteinase 9 da Matriz , Antraciclinas/efeitos adversos , Estudos de Casos e Controles , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/complicações , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/genética , Antibióticos Antineoplásicos/efeitos adversos , Miócitos Cardíacos , RNA Mensageiro , Expressão GênicaRESUMO
Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m-2: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m-2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m-2, HR: 2.33 for 300-399 mg m-2 and HR: 2.78 for ≥400 mg m-2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m-2 of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m-2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.
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Neoplasias da Mama , Policetídeos , Criança , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Antraciclinas/efeitos adversos , Doxorrubicina/efeitos adversos , Mama , DaunorrubicinaRESUMO
Anthracycline-induced cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Aberrant DNA methylation plays a role in de novo cardiovascular disease. Epigenetic processes could play a role in anthracycline-induced cardiomyopathy but remain unstudied. We sought to examine if genome-wide differential methylation at 'CpG' sites in peripheral blood DNA is associated with anthracycline-induced cardiomyopathy. This report used participants from a matched case-control study; 52 non-Hispanic White, anthracycline-exposed childhood cancer survivors with cardiomyopathy were matched 1:1 with 52 survivors with no cardiomyopathy. Paired ChAMP (Chip Analysis Methylation Pipeline) with integrated reference-based deconvolution of adult peripheral blood DNA methylation was used to analyze data from Illumina HumanMethylation EPIC BeadChip arrays. An epigenome-wide association study (EWAS) was performed, and the model was adjusted for GrimAge, sex, interaction terms of age at enrollment, chest radiation, age at diagnosis squared, and cardiovascular risk factors (CVRFs: diabetes, hypertension, dyslipidemia). Prioritized genes were functionally validated by gene knockout in human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) using CRISPR/Cas9 technology. DNA-methylation EPIC array analyses identified 32 differentially methylated probes (DMP: 15 hyper-methylated and 17 hypo-methylated probes) that overlap with 23 genes and 9 intergenic regions. Three hundred and fifty-four differential methylated regions (DMRs) were also identified. Several of these genes are associated with cardiac dysfunction. Knockout of genes EXO6CB, FCHSD2, NIPAL2, and SYNPO2 in hiPSC-CMs increased sensitivity to doxorubicin. In addition, EWAS analysis identified hypo-methylation of probe 'cg15939386' in gene RORA to be significantly associated with anthracycline-induced cardiomyopathy. In this genome-wide DNA methylation profile study, we observed significant differences in DNA methylation at the CpG level between anthracycline-exposed childhood cancer survivors with and without cardiomyopathy, implicating differential DNA methylation of certain genes could play a role in pathogenesis of anthracycline-induced cardiomyopathy.
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Cardiomiopatias , Células-Tronco Pluripotentes Induzidas , Adulto , Humanos , Antraciclinas/efeitos adversos , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Metilação de DNA , Epigênese Genética , DNA , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/genética , Ilhas de CpG , Antibióticos Antineoplásicos , Proteínas de Transporte/genética , Proteínas de Membrana/genéticaRESUMO
PURPOSE: Chemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases. PATIENTS AND METHODS: SMNs among long-term childhood cancer survivors of European (EUR; N = 9,895) and African (AFR; N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N > 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS quintiles was estimated, along with hazard ratios (HRs) from proportional hazards models. RESULTS: A total of 1,594 survivors developed SMNs, with basal cell carcinomas (n = 822), breast cancers (n = 235), and thyroid cancers (n = 221) being the most frequent. Although SMN risk associations with the PRS were extremely modest in RT-exposed EUR survivors (HR, 1.22; P = .048; n = 4,630), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant among nonirradiated EUR survivors (n = 4,322) treated with alkylating agents (17% v 6%; HR, 2.46; P < .01), anthracyclines (20% v 8%; HR, 2.86; P < .001), epipodophyllotoxins (23% v 1%; HR, 12.20; P < .001), or platinums (46% v 7%; HR, 8.58; P < .01). This PRS also significantly modified epipodophyllotoxin-related SMN risk among nonirradiated AFR survivors (n = 414; P < .01). Improvements in prediction attributable to the PRS were greatest for epipodophyllotoxin-exposed (AUC, 0.71 v 0.63) and platinum-exposed (AUC,0.68 v 0.58) survivors. CONCLUSION: A pleiotropic cancer PRS has strong potential for improving SMN clinical risk stratification among nonirradiated survivors treated with specific chemotherapies. A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer-susceptibility mutations.
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Neoplasias da Mama , Sobreviventes de Câncer , Segunda Neoplasia Primária , Adulto , Criança , Humanos , Feminino , Estudos de Coortes , Podofilotoxina , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/epidemiologia , Neoplasias da Mama/epidemiologia , Fatores de RiscoRESUMO
Background: Anthracycline-related cardiomyopathy is a leading cause of premature death in childhood cancer survivors. The high interindividual variability in risk suggests the need to understand the underlying pathogenesis. Objectives: The authors interrogated differentially expressed genes (DEGs) to identify genetic variants serving regulatory functions or genetic variants not easily identified when using genomewide array platforms. Using leads from DEGs, candidate copy number variants (CNVs) and single-nucleotide variants (SNVs) were genotyped. Methods: Messenger RNA sequencing was performed on total RNA from peripheral blood of 40 survivors with cardiomyopathy (cases) and 64 matched survivors without cardiomyopathy (control subjects). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, anthracycline dose, and chest radiation was used to assess the associations between gene expression and cardiomyopathy and between CNVs and SNVs and cardiomyopathy. Results: Haptoglobin (HP) was identified as the top DEG. Participants with higher HP gene expression had 6-fold greater odds of developing cardiomyopathy (OR: 6.4; 95% CI: 1.4-28.6). The HP2-specific allele among the HP genotypes (HP1-1, HP1-2, and HP2-2) had higher transcript levels, as did the G allele among SNVs previously reported to be associated with HP gene expression (rs35283911 and rs2000999). The HP1-2 and HP2-2 genotypes combined with the G/G genotype for rs35283911 and/or rs2000999 placed the survivors at 4-fold greater risk (OR: 3.9; 95% CI: 1.0-14.5) for developing cardiomyopathy. Conclusions: These findings provide evidence of a novel association between HP2 allele and cardiomyopathy. HP binds to free hemoglobin to form an HP-hemoglobin complex, thereby preventing oxidative damage from free heme iron, thus providing biological plausibility to the mechanistic basis of the present observation.
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PURPOSE: Cancer survivors develop cancer and treatment-related morbidities at younger than normal ages and are at risk for early mortality, suggestive of an aging phenotype. The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) is specifically designed to describe the accumulation of comorbidities over time with estimates of severity such as total score (TS) which is a sum of possible conditions weighted by severity. These severity scores can then be used to predict future mortality. METHODS: CIRS-G scores were calculated in cancer survivors and their siblings from Childhood Cancer Survivor Study cohort members from two time points 19 years apart and members of the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. CIRS-G metrics were analyzed using Cox proportional hazards regression to determine subsequent mortality risk. RESULTS: In total, 14,355 survivors with a median age of 24 (IQR, 18-30) years and 4,022 siblings with a median age of 26 (IQR, 19-33) years provided baseline data; 6,138 survivors and 1,801 siblings provided follow-up data. Cancer survivors had higher median baseline TS than siblings at baseline (5.75 v 3.44) and follow-up (7.76 v 4.79), all P < .01. The mean increase in TS from baseline to follow-up was significantly steeper in cancer survivors (2.89 males and 3.18 females) vs. siblings (1.79 males and 1.69 females) and NHANES population (2.0 males and 1.94 females), all P < .01. Every point increase in baseline TS increased hazard for death by 9% (95% CI, 8 to 10) among survivors. CONCLUSION: Application of a geriatric rating scale to characterize disease supports the hypothesis that morbidity accumulation is accelerated in young adult survivors of childhood cancer when compared with siblings and the general population.
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Sobreviventes de Câncer , Neoplasias , Masculino , Feminino , Humanos , Criança , Neoplasias/terapia , Inquéritos Nutricionais , Sobreviventes , Doença Crônica , IrmãosRESUMO
The association between individual-level poverty and relapse in children receiving maintenance treatment for acute lymphoblastic leukemia (ALL) remains unclear. In a secondary analysis of COG-AALL03N1, we used data from US Census Bureau to categorize patients living below year-specific federal poverty thresholds, calculated using self-reported annual household income and size of household. Participants with federal poverty thresholds above 120% of their yearly household income were categorized as living in extreme poverty. Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression for patients living in extreme poverty while receiving ALL maintenance therapy after adjusting for relevant predictors. Among 592 patients in this analysis, 12.3% of the patients were living in extreme poverty. After a median follow-up of 7.9 years, the cumulative incidence of relapse at 3 years from study enrollment among those living in extreme poverty was significantly higher (14.3%) than those not living in extreme poverty (7.6%). Multivariable analysis demonstrated that children living in extreme poverty had a 1.95-fold greater hazard of relapse than those not living in extreme poverty; this association was mitigated after the inclusion of race/ethnicity in the model, likely because of collinearity between race/ethnicity and poverty. A greater proportion of children living in extreme poverty were nonadherent to mercaptopurine (57.1% vs 40.9%); however, poor adherence did not completely explain the association between poverty and relapse risk. Future studies need to understand the mechanisms underlying the association between extreme poverty and relapse risk. This trial was registered at www.clinicaltrials.gov as #NCT00268528.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Mercaptopurina , Recidiva , Pobreza , IncidênciaRESUMO
PURPOSE: To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens. METHODS: Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents. RESULTS: Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity. CONCLUSION: With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.
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Sobreviventes de Câncer , Obstrução Intestinal , Neoplasias Renais , Neoplasias , Tumor de Wilms , Humanos , Criança , Neoplasias/terapia , Sobreviventes , Tumor de Wilms/terapia , Avaliação de Resultados em Cuidados de Saúde , Doença Crônica , Neoplasias Renais/terapiaRESUMO
PURPOSE: Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests a modifying role of genetic susceptibility. Few previous studies have examined gene-anthracycline interactions. We addressed this gap using the Childhood Cancer Survivor Study (discovery) and the Children's Oncology Group (COG) study COG-ALTE03N1 (replication). METHODS: A genome-wide association study (Illumina HumanOmni5Exome Array) in 1,866 anthracycline-exposed Childhood Cancer Survivor Study participants (126 with heart failure) was used to identify single-nucleotide polymorphisms (SNPs) with either main or gene-environment interaction effect on anthracycline-related cardiomyopathy that surpassed a prespecified genome-wide threshold for statistical significance. We attempted replication in a matched case-control set of anthracycline-exposed childhood cancer survivors with (n = 105) and without (n = 160) cardiomyopathy from COG-ALTE03N1. RESULTS: Two SNPs (rs17736312 [ROBO2]) and rs113230990 (near a CCCTC-binding factor insulator [< 750 base pair]) passed the significance cutoff for gene-anthracycline dose interaction in discovery. SNP rs17736312 was successfully replicated. Compared with the GG/AG genotypes on rs17736312 and anthracyclines ≤ 250 mg/m2, the AA genotype and anthracyclines > 250 mg/m2 conferred a 2.2-fold (95% CI, 1.2 to 4.0) higher risk of heart failure in discovery and an 8.2-fold (95% CI, 2.0 to 34.4) higher risk in replication. ROBO2 encodes transmembrane Robo receptors that bind Slit ligands (SLIT). Slit-Robo signaling pathway promotes cardiac fibrosis by interfering with the transforming growth factor-ß1/small mothers against decapentaplegic (Smad) pathway, resulting in disordered remodeling of the extracellular matrix and potentiating heart failure. We found significant gene-level associations with heart failure: main effect (TGF-ß1, P = .007); gene*anthracycline interaction (ROBO2*anthracycline, P = .0003); and gene*gene*anthracycline interaction (SLIT2*TGF-ß1*anthracycline, P = .009). CONCLUSION: These findings suggest that high-dose anthracyclines combined with genetic variants involved in the profibrotic Slit-Robo signaling pathway promote cardiac fibrosis via the transforming growth factor-ß1/Smad pathway, providing credence to the biologic plausibility of the association between SNP rs17736312 (ROBO2) and anthracycline-related cardiomyopathy.
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Sobreviventes de Câncer , Cardiomiopatias , Insuficiência Cardíaca , Neoplasias , Criança , Humanos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/uso terapêutico , Estudo de Associação Genômica Ampla , Antraciclinas/efeitos adversos , Neoplasias/tratamento farmacológico , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/genética , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Antibióticos Antineoplásicos/uso terapêutico , Fibrose , Receptores Imunológicos/genética , Receptores Imunológicos/uso terapêuticoRESUMO
PURPOSE: To describe the risk of late mortality, subsequent malignant neoplasms (SMNs), and chronic health conditions (CHCs) in survivors of neuroblastoma diagnosed in infancy by treatment era and exposures. METHODS: Among 5-year survivors of neuroblastoma in the Childhood Cancer Survivor Study diagnosed age < 1 year between 1970 and 1999, we examined the cumulative incidence of late (> 5 years from diagnosis) mortality, SMN, and CHCs (grades 2-5 and 3-5). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs by decade and treatment (surgery-alone v chemotherapy with or without surgery [C ± S] v radiation with or without chemotherapy ± surgery [R ± C ± S]) among survivors and between survivors and 5,051 siblings. RESULTS: Among 1,397 eligible survivors, the 25-year cumulative incidence of late mortality was 2.1% (95% CI, 1.3 to 3.9) with no difference by treatment era. Among 990 participants who completed a baseline survey, fewer survivors received radiation in more recent eras (51.2% 1970s, 20.4% 1980s, and 10.1% 1990s; P < .001). Risk of SMN was elevated only among individuals treated with radiation-containing regimens compared with surgery alone (HR[C ± S], 3.2 [95% CI, 0.9 to 11.6]; HR[R ± C ± S], 5.7 [95% CI, 1.2 to 28.1]). In adjusted models, there was a 50% reduction in risk of grade 3-5 CHCs in the 1990s versus 1970s (HR, 0.5 [95% CI, 0.3 to 0.9]; P = .01); individuals treated with radiation had a 3.6-fold risk for grade 3-5 CHCs (95% CI, 2.1 to 6.2) versus those treated with surgery alone. When compared with siblings, risk of grade 3-5 CHCs for survivors was lowest in the most recent era (HR[1970s], 4.7 [95% CI, 3.4 to 6.5]; HR[1980s], 4.6 [95% CI, 3.3 to 6.4]; HR[1990s], 2.5 [95% CI, 1.7 to 3.9]). CONCLUSION: Neuroblastoma survivors treated during infancy have a relatively low absolute burden of late mortality and SMN. Encouragingly, risk of CHCs has declined in more recent eras with reduced exposure to radiation therapy.
Assuntos
Sobreviventes de Câncer , Segunda Neoplasia Primária , Neuroblastoma , Criança , Lactente , Humanos , Estudos Retrospectivos , Sobreviventes , Neuroblastoma/epidemiologia , Neuroblastoma/terapia , Morbidade , Incidência , Segunda Neoplasia Primária/epidemiologiaRESUMO
Five-year survival following childhood acute myeloid leukemia (AML) has increased following improvements in treatment and supportive care. Long-term health outcomes are unknown. To address this, cumulative incidence of late mortality and grades 3 to 5 chronic health condition (CHC) were estimated among 5-year AML survivors diagnosed between 1970 and 1999. Survivors were compared by treatment group (hematopoietic cell transplantation [HCT], chemotherapy with cranial radiation [chemo + CRT], chemotherapy only [chemo-only]), and diagnosis decade. Self-reported health status was compared across treatments, diagnosis decade, and with siblings. Among 856 survivors (median diagnosis age, 7.1 years; median age at last follow-up, 29.4 years), 20-year late mortality cumulative incidence was highest after HCT (13.9%; 95% confidence interval [CI], 10.0%-17.8%; chemo + CRT, 7.6%; 95% CI, 2.2%-13.1%; chemo-only, 5.1%; 95% CI, 2.8%-7.4%). Cumulative incidence of mortality for HCT survivors diagnosed in the 1990s (8.5%; 95% CI, 4.1%-12.8%) was lower vs those diagnosed in the 1970s (38.9%; 95% CI, 16.4%-61.4%). Most survivors did not experience any grade 3 to 5 CHC after 20 years (HCT, 45.8%; chemo + CRT, 23.7%; chemo-only, 27.0%). Furthermore, a temporal reduction in CHC cumulative incidence was seen after HCT (1970s, 76.1%; 1990s, 38.3%; P = .02), mirroring reduced use of total body irradiation. Self-reported health status was good to excellent for 88.2% of survivors; however, this was lower than that for siblings (94.8%; P < .0001). Although HCT is associated with greater long-term morbidity and mortality than chemotherapy-based treatment, gaps have narrowed, and all treatment groups report favorable health status.
Assuntos
Sobreviventes de Câncer , Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Humanos , Criança , Adulto , Avaliação de Resultados em Cuidados de Saúde , Nível de Saúde , Leucemia Mieloide Aguda/terapia , Doença CrônicaRESUMO
PURPOSE: To evaluate the outcomes and cost-effectiveness of the Children's Oncology Group Guideline recommendation for breast cancer (BC) screening using mammography (MAM) and breast magnetic resonance imaging (MRI) in female chest-irradiated childhood Hodgkin lymphoma (HL) survivors. Digital breast tomosynthesis (DBT), increasingly replacing MAM in practice, was also examined. METHODS: Life years (LYs), quality-adjusted LYs (QALYs), BC mortality, health care costs, and false-positive screen frequencies of undergoing annual MAM, DBT, MRI, MAM + MRI, and DBT + MRI from age 25 to 74 years were estimated by microsimulation. BC risks and non-BC mortality were estimated from female 5-year survivors of HL in the Childhood Cancer Survivor Study and the US population. Test performance of MAM and MRI was synthesized from HL studies, and that of DBT from the general population. Costs (2017 US dollars [USD]) and utility weights were obtained from the medical literature. Incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: With 100% screening adherence, annual BC screening extended LYs by 0.34-0.46 years over no screening. If the willingness-to-pay threshold to gain a quality-adjusted LY was ICER < $100,000 USD, annual MAM at age 25-74 years was the only cost-effective strategy. When nonadherence was taken into consideration, only annual MAM at age 30-74 years (ICER = $56,972 USD) was cost-effective. Supplementing annual MAM with MRI costing $545 USD was not cost-effective under either adherence condition. If MRI costs were reduced to $300 USD, adding MRI to annual MAM at age 30-74 years could become more cost-effective, particularly in the reduced adherence condition (ICER = $133,682 USD). CONCLUSION: Annual BC screening using MAM at age 30-74 years is effective and cost-effective in female chest-irradiated HL survivors. Although annual adjunct MRI is not cost-effective at $545 USD cost, it could become cost-effective as MRI cost is reduced, a plausible scenario with the emergent use of abbreviated MRI.
Assuntos
Neoplasias da Mama , Doença de Hodgkin , Humanos , Feminino , Criança , Adulto , Pessoa de Meia-Idade , Idoso , Neoplasias da Mama/diagnóstico , Análise Custo-Benefício , Detecção Precoce de Câncer/métodos , Mamografia , Sobreviventes , Programas de RastreamentoRESUMO
BACKGROUND: Obesity at diagnosis of childhood acute lymphoblastic leukemia (ALL) is associated with greater risk of relapse; whether this association extends to obesity during maintenance is unstudied. METHODS: This study used data from AALL03N1 to calculate median body mass index (BMI) for 676 children over 6 consecutive months during maintenance therapy; BMI percentile (BMI%ile) were operationalized as normal/underweight (<85%ile), overweight/obese (85%-98%ile), and extreme obesity (≥99%ile). Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression after adjusting for all relevant demographic and clinical predictors. RESULTS: Median age at study enrollment was 6 years and median length of follow-up was 7.9 years. Overall, 43.3% of the cohort was underweight/normal weight, 44.8% was overweight/obese, and 11.8% had extreme obesity. Cumulative incidence of relapse at 4 years from study enrollment was higher among those with extreme obesity (13.6% ± 4.5%) compared to those with underweight/normal weight (9.0% ± 2.1%). Multivariable analysis revealed that children with extreme obesity had a 2.4-fold (95% confidence interval [CI], 1.1-5.0; p = .01) greater hazard of relapse compared to those who were underweight/normal weight. Overweight/obese patients were at comparable risk to those who were underweight/normal weight (hazard ratio, 0.8; 95% CI, 0.4-1.6). Erythrocyte thioguanine nucleotide (TGN) levels were significantly lower among children with extreme obesity compared to those with underweight/normal weight (141.6 vs. 168.8 pmol/8 × 108 erythrocytes; p = .0002), however, the difference in TGN levels did not explain the greater hazard of relapse among those with extreme obesity. CONCLUSIONS: Extreme obesity during maintenance therapy is associated with greater hazard of relapse in children with ALL. Underlying mechanisms of this association needs further investigation. LAY SUMMARY: Findings from this study demonstrate that extreme obesity during maintenance therapy is associated with a greater hazard of relapse among children with acute lymphoblastic leukemia. We show that children with obesity have lower levels of erythrocyte thioguanine nucleotides even after adjusting for adherence to oral chemotherapy. However, these lower levels do not explain the greater hazard of relapse, paving the way for future studies to explore this association.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Índice de Massa Corporal , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Sobrepeso/complicações , Sobrepeso/epidemiologia , Magreza/complicações , Obesidade/complicações , Obesidade/epidemiologia , Tioguanina , RecidivaRESUMO
PURPOSE: The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer was established in 2018 to address gaps in knowledge of risk and risk factors for breast cancer subsequent to childhood/adolescent cancer by pooling individual patient data from seven cohorts. Initially, the pooled cohort will focus on three clinically relevant questions regarding treatment-related subsequent breast cancer risk in female survivors, which are the risk related to low-dose radiotherapy exposure to the chest, specific chemotherapy agents and attained age. PARTICIPANTS: The consortium database includes pooled data on 21 892 female survivors from seven cohorts in North America and Europe with a primary cancer diagnosis at <21 years of age, and survival ≥5 years from diagnosis. FINDINGS TO DATE: This is a newly established pooled study. The cohort profile summarised the data collected from each included cohort, including childhood cancer diagnosis information and treatment details (ie, radiotherapy fields and cumulative doses, and chemotherapy agents and cumulative doses for each agent). Included cohorts' follow-up started 1951-1981 and ended 2013-2021, respectively, for a median follow-up duration of 24.3 (IQR 18.0-32.8) years since primary cancer diagnosis. The median age at primary cancer diagnosis was 5.4 (IQR 2.5-11.9) years. And the median attained age at last follow-up was 32.2 (IQR 24.0-40.4) years. In all, 4240 (19.4%) survivors were treated with radiotherapy to the chest and 9308 (42.5%) with anthracyclines. At the end of the follow-up, 835 females developed a first subsequent breast cancer, including 635 invasive breast cancer only, 184 carcinomas in situ only (172 ductal carcinomas in situ and 12 lobular carcinomas in situ), and 16 with both an invasive and in situ diagnosis at the same moment. The cumulative incidences of subsequent breast cancer (both invasive and in situ) 25 and 35 years after primary cancer diagnosis were 2.2% and 6.2%, respectively. FUTURE PLANS: The consortium is intended to serve as a model and robust source of childhood/adolescent cancer survivor data for elucidating other knowledge gaps on subsequent breast cancer risk, and risk of other subsequent malignancies (including data on males) in the future.