Press Release: Childhood Cancer Survivors at Increased Risk of Sarcoma

Abstract Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

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Identification of Biochemical and Molecular Markers of Early Aging in Childhood Cancer Survivors

10.1101/2021.04.01.438017 ◽

2021 ◽

Author(s):

Silvia Ravera ◽

Tiziana Vigliarolo ◽

Silvia Bruno ◽

Fabio Morandi ◽

Danilo Marimpietri ◽

...

Keyword(s):

Cancer Survivors ◽

Childhood Cancer ◽

Childhood Cancer Survivors ◽

Antioxidant Defenses ◽

Elderly Subjects ◽

Cancer Type ◽

Metabolism Regulation ◽

Increased Risk ◽

Early Aging ◽

The Impact

ABSTRACTPurposeSurvival rates of Childhood Cancer Patients have improved tremendously over the past four decades. However, cancer treatments are associated with an increased risk of developing an anticipated onset of chronic diseases typical of aging. Thus, we aimed to identify molecular/metabolic cellular alterations responsible for early aging in Childhood Cancer Survivors (CCS).Patients and MethodsBiochemical, proteomic and molecular biology analyses were conducted on mononuclear cells (MNCs) isolated from peripheral blood of 196 CCS, comparing the results with those obtained on MNCs of 154 healthy subjects.ResultsData demonstrate that CCS-MNCs show: i) inefficient oxidative phosphorylation associated with low energy status and a metabolic switch to lactate fermentation compared with age-matched normal controls; ii) increment of lipid peroxidation due to an unbalance among the oxidative stress production and the activation of the antioxidant defenses; (iii) significantly lower expression of genes and proteins involved in mitochondrial biogenesis and metabolism regulation, such as CLUH, PGC1-α, and SIRT6 in CCS, not observed in the age-matched healthy or elderly subjects. The application of a mathematical model based on biochemical parameters predicts that CCS have a biological age significantly increased by decades compared to the chronological age. Overall, the results show that the impact of chemo/chemoradiotherapy on mitochondria efficiency in 196 CCS was rather homogeneous, irrespective of cancer type, treatment protocols, and time elapsed from the end of the curative period.ConclusionsOur study identifies some biochemical and molecular alterations possibly contributing to the pathophysiology of anticipated aging and metabolic deficiency described in CCS. These results may be useful in identifying approaches to restore the mitochondrial function, slowing down the aging and the associated pathological conditions in CCS.

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Genetic and treatment risks for diabetes mellitus (DM) in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS) and St. Jude Lifetime (SJLIFE) cohorts.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10014 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10014-10014

Author(s):

Melissa A. Richard ◽

Sogol Mostoufi-Moab ◽

Nisha Rathore ◽

Austin L. Brown ◽

Stephen J. Chanock ◽

...

Keyword(s):

Risk Factors ◽

Cancer Survivors ◽

Cancer Treatment ◽

Childhood Cancer ◽

Regulatory Region ◽

Childhood Cancer Survivors ◽

Population Based ◽

European Ancestry ◽

Radiation Group ◽

Increased Risk

10014 Background: Childhood cancer survivors face increased risk for DM, a polygenic trait also attributable to cancer treatment exposures, particularly abdominal radiation. We aimed to characterize the role of genetic and treatment risk factors for DM among two large cohorts of childhood cancer survivors. Methods: We performed a nested case-control genome-wide association study for DM managed with oral medications in the original CCSS cohort (diagnosed 1970-1986). Logistic regression was conducted in the total sample (N = 5083) and stratified by 1) European ancestry (EA) and 2) abdominal radiation. Replication of suggestive variants (P < 1×10-7) using Fisher’s exact test was performed in independent cohorts: i) CCSS expansion diagnosed 1987-1999 (N = 2588) and ii) SJLIFE diagnosed 1962-2012 (N = 2182). To evaluate the effect of cancer treatment on the background genetic predisposition to DM, we estimated standardized effect sizes (Z’) among EA survivors in each abdominal radiation group for 398 index variants from the largest population-based EA DM study. Radiation group Z’ estimates were compared using linear regression. Results: In the original CCSS cohort we identified nine variants associated with DM and provide further support for four linked variants in the ERCC6L2 locus. Among all survivors, the rs55849673-A allele was associated with increased odds for DM among survivors in the original CCSS cohort (minor allele frequency [MAF]-cases = 0.055; MAF-controls = 0.024; adjusted odds ratio [aOR] = 2.9, 95% CI: 2.0-4.2, P = 3.7×10-8). Allele frequencies were consistent in the CCSS expansion (MAF-cases = 0.075; MAF-controls = 0.028; P = 0.07) and SJLIFE (MAF-cases = 0.036; MAF-controls = 0.027; P = 0.5). Additionally, rs55849673-A estimates were consistent among EA survivors and stronger among survivors not treated with abdominal radiation (MAF-cases = 0.052; MAF-controls = 0.021; aOR = 3.6, P = 1.6×10-6). Notably, in the CCSS expansion all rs55849673-A EA carriers who developed DM did not receive abdominal radiation (MAF-cases = 0.1; MAF-controls = 0.026; P = 0.04). More broadly, the Z’ of population-based DM index variants were 78% lower in survivors treated with abdominal radiation than survivors not treated with abdominal radiation (beta = 0.22; P = 0.01), indicating the background genetic risk for DM may be altered by treatment. Conclusions: We provide evidence for a novel locus of DM in childhood cancer survivors. This locus is a regulatory region associated with expression of ERCC6L2, a gene implicated in an East Asian population-based DM study. Taken together, our findings support the overwhelming effect of abdominal radiation on DM risk in childhood cancer survivors, relative to other risk factors, and provide insight on a genetic locus that may be useful for DM risk prediction in the context of cancer treatment.

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Increased Risk of All Cardiovascular Disease Subtypes Among Childhood Cancer Survivors

Circulation ◽

10.1161/circulationaha.119.041403 ◽

2019 ◽

Vol 140 (12) ◽

pp. 1041-1043 ◽

Cited By ~ 5

Author(s):

Ashna Khanna ◽

Priscila Pequeno ◽

Sumit Gupta ◽

Paaladinesh Thavendiranathan ◽

Douglas S. Lee ◽

...

Keyword(s):

Cardiovascular Disease ◽

Cancer Survivors ◽

Childhood Cancer ◽

Childhood Cancer Survivors ◽

Increased Risk ◽

Disease Subtypes

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Subsequent Neoplasms After a Primary Tumor in Individuals With Neurofibromatosis Type 1

Journal of Clinical Oncology ◽

10.1200/jco.19.00114 ◽

2019 ◽

Vol 37 (32) ◽

pp. 3050-3058 ◽

Cited By ~ 6

Author(s):

Smita Bhatia ◽

Yanjun Chen ◽

F. Lennie Wong ◽

Lindsey Hageman ◽

Kandice Smith ◽

...

Keyword(s):

Cancer Survivors ◽

Childhood Cancer ◽

Primary Tumor ◽

Alkylating Agents ◽

Neurofibromatosis Type ◽

Childhood Cancer Survivors ◽

University Of Alabama ◽

Primary Tumors ◽

Increased Risk ◽

Childhood Cancer Survivor Study

PURPOSE Fundamental gaps in knowledge regarding the risk of subsequent neoplasms (SNs) in children with pathogenic neurofibromatosis type 1 (NF1) variants exposed to radiation and/or alkylator chemotherapy have limited the use of these agents. METHODS We addressed these gaps by determining the SN risk in 167 NF1-affected versus 1,541 non–NF1-affected 5-year childhood cancer survivors from the Childhood Cancer Survivor Study and 176 nonoverlapping NF1-affected individuals with primary tumors from University of Alabama at Birmingham and Children’s Hospital of Philadelphia exposed to radiation and/or chemotherapy. Proportional subdistribution hazards multivariable regression analysis was used to examine risk factors, adjusting for type and age at primary tumor diagnosis and therapeutic exposures. RESULTS In the Childhood Cancer Survivor Study cohort, the 20-year cumulative incidence of SNs in NF1 childhood cancer survivors was 7.3%, compared with 2.9% in the non-NF1 childhood cancer survivors ( P = .003), yielding a 2.4-fold higher risk of SN (95% CI, 1.3 to 4.3; P = .005) in the NF1-affected individuals. In the University of Alabama at Birmingham and Children’s Hospital of Philadelphia cohort, among NF1-affected individuals with a primary tumor, the risk of SNs was 2.8-fold higher in patients with irradiated NF1 (95% CI, 1.3 to 6.0; P = .009). In contrast, the risk of SNs was not significantly elevated after exposure to alkylating agents (hazard ratio, 1.27; 95% CI, 0.3 to 3.0; P = .9). CONCLUSION Children with NF1 who develop a primary tumor are at increased risk of SN when compared with non-NF1 childhood cancer survivors. Among NF1-affected children with a primary tumor, therapeutic radiation, but not alkylating agents, confer an increased risk of SNs. These findings can inform evidence-based clinical management of primary tumors in NF1-affected children.

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Predicting and Preventing Anthracycline-Related Cardiotoxicity

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_100015 ◽

2018 ◽

pp. 3-12 ◽

Cited By ~ 21

Author(s):

Saro Armenian ◽

Smita Bhatia

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Cancer Survivors ◽

Childhood Cancer ◽

Prediction Models ◽

Lymphoblastic Leukemia ◽

Childhood Cancer Survivors ◽

Chemotherapeutic Agents ◽

Increased Risk ◽

Risk Reducing

Anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) are among the most potent chemotherapeutic agents and have truly revolutionized the management of childhood cancer. They form the backbone of chemotherapy regimens used to treat childhood acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin lymphoma, Ewing sarcoma, osteosarcoma, and neuroblastoma. More than 50% of children with cancer are treated with anthracyclines. The clinical utility of anthracyclines is compromised by dose-dependent cardiotoxicity, manifesting initially as asymptomatic cardiac dysfunction and evolving irreversibly to congestive heart failure. Childhood cancer survivors are at a five- to 15-fold increased risk for congestive heart failure compared with the general population. Once diagnosed with congestive heart failure, the 5-year survival rate is less than 50%. Prediction models have been developed for childhood cancer survivors (i.e., after exposure to anthracyclines) to identify those at increased risk for cardiotoxicity. Studies are currently under way to test risk-reducing strategies. There remains a critical need to identify patients with childhood cancer at diagnosis (i.e., prior to anthracycline exposure) such that noncardiotoxic therapies can be contemplated.

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Managing childhood cancer survivors at risk for stroke: Practice norms and areas of controversy.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.7_suppl.124 ◽

2018 ◽

Vol 36 (7_suppl) ◽

pp. 124-124 ◽

Cited By ~ 1

Author(s):

Lisa Brazzamano Kenney ◽

Bethany Ames ◽

Alexis L. Michaud ◽

David Williams ◽

Nicole A. Ullrich ◽

...

Keyword(s):

At Risk ◽

Cancer Survivors ◽

Acute Stroke ◽

Childhood Cancer ◽

Stroke Prevention ◽

Childhood Cancer Survivors ◽

Large Vessel ◽

Small Vessel ◽

Clinical Scenarios ◽

Increased Risk

124 Background: Childhood cancer survivors (CCS) treated with cranial radiation (CR) are at increased risk for stroke. There is no evidence to guide stroke prevention strategies for CSS. We aimed to describe regional practice norms for managing survivors at risk for stroke and to define areas where management is controversial. Methods: We conducted a Delphi panel of 30 physicians from the New England region who care for CCS, including primary care and specialists. Panelists anonymously answered 3 rounds of open ended questionnaires querying their management approach to a childhood brain tumor survivor treated with CR formatted as 5 clinical scenarios (asymptomatic, large and small vessel cerebral vascular disease (CVD), TIA, stroke), covering 5 categories of management (imaging, lab testing, medication, counseling, referrals). Consensus was defined as ≥ 90% of panelist agreeing with management option. Results: There was a 100% response rate for all 3 rounds of questionnaires. Of the 25 management questions related to 5 clinical scenarios, consensus was reached on 18 while 7 remained controversial. In the scenario of acute stroke symptoms, consensus was reached in all 5 categories of management. In the scenarios of large vessel CVD with symptoms of a TIA, large-vessel CVD without symptoms, and small-vessel CVD without symptoms panelists did not reach consensus on medication, specifically, aspirin use. The primary reasons for disagreement were no evidence for benefit/risk and beyond area of expertise. In the scenario of an asymptomatic survivor with no history of CVD panelists did not reach consensus on indication for MRI surveillance imaging, the primary reasons for disagreement were no clear benefit and risk of findings with uncertain clinical significance. Consensus was not reached on specialty referral patterns in any scenario except acute stroke. Conclusions: Despite lack of evidence to guide stroke prevention in childhood cancer survivors treated with CR, a panel of regional physicians reached consensus on managing most clinical scenarios. Controversial areas requiring further study are follow-up imaging for asymptomatic survivors, aspirin for stroke prophylaxis, and indications for sub-specialty referral.

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Increased risk of thyroid dysfunction in childhood cancer survivors

Nature Clinical Practice Endocrinology &#38 Metabolism ◽

10.1038/ncpendmet0570 ◽

2007 ◽

Vol 3 (9) ◽

pp. 618-618

Keyword(s):

Cancer Survivors ◽

Childhood Cancer ◽

Thyroid Dysfunction ◽

Childhood Cancer Survivors ◽

Increased Risk

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Cardiovascular Status of Childhood Cancer Survivors Exposed and Unexposed to Cardiotoxic Therapy

Journal of Clinical Oncology ◽

10.1200/jco.2010.33.7907 ◽

2012 ◽

Vol 30 (10) ◽

pp. 1050-1057 ◽

Cited By ~ 95

Author(s):

Steven E. Lipshultz ◽

David C. Landy ◽

Gabriela Lopez-Mitnik ◽

Stuart R. Lipsitz ◽

Andrea S. Hinkle ◽

...

Keyword(s):

Cancer Survivors ◽

Childhood Cancer ◽

Systemic Inflammation ◽

Wall Thickness ◽

Childhood Cancer Survivors ◽

Left Ventricular ◽

Atherosclerotic Disease ◽

Cardiovascular Abnormalities ◽

Increased Risk ◽

Lv Mass

Purpose To determine whether cardiovascular abnormalities in childhood cancer survivors are restricted to patients exposed to cardiotoxic anthracyclines and cardiac irradiation and how risk factors for atherosclerotic disease and systemic inflammation contribute to global cardiovascular status. Methods We assessed echocardiographic characteristics and atherosclerotic disease risk in 201 survivors of childhood cancer with and without exposure to cardiotoxic treatments at a median of 11 years after diagnosis (range, 3 to 32 years) and in 76 sibling controls. Results The 156 exposed survivors had below normal left ventricular (LV) mass, wall thickness, contractility, and fractional shortening and above normal LV afterload. The 45 unexposed survivors also had below normal LV mass overall, and females had below normal LV wall thickness. Exposed and unexposed survivors, compared with siblings, had higher levels of N-terminal pro-brain natriuretic peptide (81.7 and 69.0 pg/mL, respectively, v 39.4 pg/mL), higher mean fasting serum levels of non–high-density lipoprotein cholesterol (126.5 and 121.1 mg/dL, respectively, v 109.8 mg/dL), higher insulin levels (10.4 and 10.5 μU/mL, respectively, v 8.2 μU/mL), and higher levels of high-sensitivity C-reactive protein (2.7 and 3.1 mg/L, respectively, v 0.9 mg/L; P < .001 for all comparisons). Age-adjusted, predicted-to-ideal 30-year risk of myocardial infarction, stroke, or coronary death was also higher for exposed and unexposed survivors compared with siblings (2.16 and 2.12, respectively, v 1.70; P < .01 for both comparisons). Conclusion Childhood cancer survivors not receiving cardiotoxic treatments nevertheless have cardiovascular abnormalities, systemic inflammation, and an increased risk of atherosclerotic disease. Survivorship guidelines should address cardiovascular concerns, including the risk of atherosclerotic disease and systemic inflammation, in exposed and unexposed survivors.

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