Publications by authors named "Sharon M Castellino"

54 Publications

Racial Disparities in Children, Adolescents, and Young Adults with Hodgkin Lymphoma Enrolled in the New York State Medicaid Program.

J Adolesc Young Adult Oncol 2021 Oct 8. Epub 2021 Oct 8.

Center for Oncology Hematology Outcomes Research and Training (COHORT) and Division of Hematology and Oncology, University of California Davis School of Medicine, Sacramento, California, USA.

We examined the impact of race/ethnicity and age on survival in a publicly insured cohort of children and adolescent/young adults (AYA; 15-39 years) with Hodgkin lymphoma, adjusting for chemotherapy using linked Medicaid claims. We identified 1231 Medicaid-insured patients <1-39 years diagnosed with classical Hodgkin lymphoma between 2005 and 2015, in the New York State Cancer Registry. Chemotherapy regimens were based on contemporary therapeutic regimens. Cox proportional hazards regression models quantified associations of patient, disease, and treatment variables with overall survival (OS) and disease-specific survival (DSS), and are presented as hazard ratios (HR) with confidence intervals (95% CIs). At median follow-up of 6.6 years,  = 1108 (90%) patients were alive; 5-year OS was 92% in children <15 years. In multivariable models, Black (vs. White) patients had 1.6-fold increased risk of death (HR: 1.58, 95% CI: 1.02-2.46;  = 0.042). Stage III/IV (vs. I/II) was associated with 1.9-fold increased risk of death (HR: 1.86, 95% CI: 1.25-2.78;  = 0.002) and treatment at a non-National Cancer Institute (NCI) affiliate was associated with worse DSS (HR: 2.71, 95% CI: 1.47-4.98;  = 0.001). In this Medicaid-insured cohort of children and AYAs with Hodgkin lymphoma, Black race/ethnicity remained associated with inferior OS in multivariable models adjusted for disease, demographic, and treatment data. Further work is needed to identify dimensions of health care access not mediated by insurance, as findings suggest additional factors are contributing to observed cancer disparities in vulnerable pediatric and AYA populations.
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http://dx.doi.org/10.1089/jayao.2021.0131DOI Listing
October 2021

Multicenter Analysis of Genomically Targeted Single Patient Use Requests for Pediatric Neoplasms.

J Clin Oncol 2021 Sep 30:JCO2101213. Epub 2021 Sep 30.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: The US Food and Drug Administration-expanded access program (EAP) uses a single patient use (SPU) mechanism to provide patient access to investigational agents in situations where no satisfactory or comparable therapy is available. Genomic profiling of de novo and relapsed or refractory childhood cancer has led to increased identification of new drug targets in the last decade. The aim of this study is to examine the SPU experience for genomically targeted therapies in patients with pediatric cancer.

Patients And Methods: All genomically targeted therapeutic SPUs obtained over a 5-year period were evaluated at four large pediatric cancer programs. Data were collected on the type of neoplasm, agents requested, corresponding molecularly informed targets, and clinical outcomes.

Results: A total of 45 SPUs in 44 patients were identified. Requests were predominantly made for CNS and solid tumors (84.4%) compared with hematologic malignancies (15.6%). Lack of an available clinical trial was the main reason for SPU initiation (64.4%). The median time from US Food and Drug Administration submission to approval was 3 days (range, 0-12 days) and from Institutional Review Board submission to approval was 5 days (range, 0-50 days). Objective tumor response was seen in 39.5% (15 of 38) of all evaluable SPUs. Disease progression was the primary reason for discontinuation of drug (66.7%) followed by toxicity (13.3%).

Conclusion: SPU requests remain an important mechanism for pediatric access to genomically targeted agents given the limited availability of targeted clinical trials for children with high-risk neoplasms. Furthermore, this subset of SPUs resulted in a substantial number of objective tumor responses. The development of a multi-institutional data registry of SPUs may enable systematic review of toxicity and clinical outcomes and provide evidence-based access to new drugs in rare pediatric cancers.
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http://dx.doi.org/10.1200/JCO.21.01213DOI Listing
September 2021

Evaluating Palliative Opportunities Across the Age Spectrum in Children and Adolescent Patients with Cancer.

J Adolesc Young Adult Oncol 2021 Sep 28. Epub 2021 Sep 28.

Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Atlanta, Georgia, USA.

Adolescent patients with cancer experience unique stressors due to their developmental stage, with increased physical, emotional, and social distress. Palliative care (PC) serves an important role in pediatric cancer care. We examined "palliative opportunities," or events during a patient's cancer course where subspecialty PC would be warranted and compared opportunities between adolescents and younger patients. Patients from a single center, 0-18 years of age at cancer diagnosis, who died from January 1, 2012, to November 30, 2017, were included. In this secondary analysis, patients were divided into cohorts based on age at diagnosis: 0-12 and 13-18 years. Demographic, disease, and treatment data were collected. Descriptive statistics and modeling were performed. Number, type, and timing of palliative opportunities and PC consultation timing and reason were evaluated across cohorts. Of the 296 patients included for analysis, 27.7% were 13-18 years (82/296) at diagnosis. Frequency of palliative opportunities did not differ by age (median 7.0 [interquartile range 4.0 and 10.0] in both cohorts). PC consultation occurred in 36.5% (108/296), with neither rate nor timing differing by age group. PC consultations in adolescents were more often for symptom management ( = 0.0001). Adolescent patients were less likely to have a do-not-resuscitate order placed before death (61.0%, 50/82) compared to younger patients (73.8%, 158/214,  = 0.03). Adolescent patients with cancer did not experience more palliative opportunities than younger patients in this cohort, although they often have challenging psychological, family, and social stressors that were not identified. Incorporating additional palliative opportunities could enhance identification of stress and symptoms in adolescents with cancer such that PC could be timed to meet their needs.
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http://dx.doi.org/10.1089/jayao.2021.0081DOI Listing
September 2021

Late hepatic toxicity surveillance for survivors of childhood, adolescent and young adult cancer: Recommendations from the international late effects of childhood cancer guideline harmonization group.

Cancer Treat Rev 2021 Nov 20;100:102296. Epub 2021 Sep 20.

Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.

Background: Survivors of childhood, adolescent and young adult (CAYA) cancer may develop treatment-induced chronic liver disease. Surveillance guidelines can improve survivors' health outcomes. However, current recommendations vary, leading to uncertainty about optimal screening. The International Late Effects of Childhood Cancer Guideline Harmonization Group has developed recommendations for the surveillance of late hepatotoxicity after CAYA cancer.

Methods: Evidence-based methods based on the GRADE framework were used in guideline development. A multidisciplinary guideline panel performed systematic literature reviews, developed evidence summaries, appraised the evidence, and formulated recommendations on the basis of evidence, clinical judgement, and consideration of benefits versus the harms of the surveillance while allowing for flexibility in implementation across different health care systems.

Results: The guideline strongly recommends a physical examination and measurement of serum liver enzyme concentrations (ALT, AST, gGT, ALP) once at entry into long-term follow-up for survivors treated with radiotherapy potentially exposing the liver (moderate- to high-quality evidence). For survivors treated with busulfan, thioguanine, mercaptopurine, methotrexate, dactinomycin, hematopoietic stem cell transplantation (HSCT), or hepatic surgery, or with a history of chronic viral hepatitis or sinusoidal obstruction syndrome, similar surveillance for late hepatotoxicity once at entry into LTFU is reasonable (low-quality evidence/expert opinion, moderate recommendation). For survivors who have undergone HSCT and/or received multiple red blood cell transfusions, surveillance for iron overload with serum ferritin is strongly recommended once at long-term follow-up entry.

Conclusions: These evidence-based, internationally-harmonized recommendations for the surveillance of late hepatic toxicity in cancer survivors can inform clinical care and guide future research of health outcomes for CAYA cancer survivors.
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http://dx.doi.org/10.1016/j.ctrv.2021.102296DOI Listing
November 2021

Integration of Pediatric Hodgkin Lymphoma Treatment and Late Effects Guidelines: Seeing the Forest Beyond the Trees.

J Natl Compr Canc Netw 2021 06 30;19(6):755-764. Epub 2021 Jun 30.

1Department of Oncology, and.

The successful integration of clinical trials into pediatric oncology has led to steady improvement in the 5-year survival rate for children diagnosed with Hodgkin lymphoma (HL). It is estimated that >95% of children newly diagnosed with HL will become long-term survivors. Despite these successes, survival can come at a cost. Historically, long-term survivors of HL have a high risk of late-occurring adverse health effects and increased risk of nonrelapse mortality compared with the general population. The recognition of late-occurring events paired with the decades of life remaining for children cured of HL have made paramount the need to develop effective treatments that minimize the risk of late toxicity. Toward this goal, multiple, dose-intense, risk- and response-based regimens that use lower cumulative doses of chemotherapy and radiation have been developed. Appropriate frontline treatment selection requires a level of familiarity with the efficacy, acute toxicity, convenience, and late effects of treatments that may be impractical for providers who infrequently treat children with HL. There is an increasing need for guideline developers to begin to merge considerations from both frontline treatment and survivorship guidelines into practical documents that integrate potential long-term health risks. Herein, we take the first steps toward doing so by aligning cumulative treatment exposures, anticipated risks of late toxicity, and suggested surveillance recommendations for NCCN-endorsed Pediatric HL Guidelines. Future studies that integrate simulation modeling will strengthen this integrated approach and allow for opportunities to incorporate regimen-specific risks, health-related quality of life, and cost-effectiveness into decision tools to optimize HL therapy.
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http://dx.doi.org/10.6004/jnccn.2021.7042DOI Listing
June 2021

Patients, caregivers, and clinicians differ in performance status ratings: Implications for pediatric cancer clinical trials.

Cancer 2021 Oct 1;127(19):3664-3670. Epub 2021 Jul 1.

Children's Hospital Los Angeles, Los Angeles, California.

Background: The Lansky Play-Performance Scale (LPPS) is often used to determine a child's performance status for cancer clinical trial eligibility. Differences between clinician and caregiver LPPS ratings and their associations with child-reported functioning have not been evaluated.

Methods: Children aged 7 to 18 years who were receiving cancer treatment and their caregivers were recruited from 9 pediatric cancer centers. Caregivers and clinicians reported LPPS scores, and children completed Patient-Reported Outcomes Measurement Information System (PROMIS) pediatric functioning and symptom measures before treatment (time 1 [T1]) and after treatment (time 2 [T2]). t tests and mixed-linear models were used to assess differences in caregiver and clinician LPPS scores; polyserial correlations quantified associations between PROMIS and LPPS scores.

Results: Of 482 children, 281 had matched caregiver- and clinician-reported LPPS T1/T2 scores. Caregivers rated children significantly worse on the LPPS than clinicians at both T1 (mean, 73.3 vs 87.4; P < .01) and T2 (mean, 67.9 vs 83.1; P < .01). These differences were not related to a child's age (P = .89), diagnosis (P = .17), or sex (P = .64) or to the time point (P = .45). Small to moderate associations existed between caregiver- and clinician-reported LPPS ratings and child-reported PROMIS scores for mobility (caregiver T1/T2 r = 0.51/0.45; P < .01; clinician T1/T2 r = 0.40/0.35; P < .01), fatigue (caregiver T1/T2 r = -0.46/-0.37; P < .01; clinician T1/T2 r = -0.26/-0.27; P < .01), and pain interference (caregiver T1/T2 r = -0.32/-0.30; P < .01; clinician T1/T2 r = -0.17/-0.31; P < .01). Caregivers and clinicians assigned significantly lower LPPS scores at T2 (caregiver Δ = -5.37; P < .01; clinician Δ = -4.20; P < .01), whereas child-reported PROMIS scores were clinically stable.

Conclusions: Significant differences between clinician and caregiver LPPS ratings of child performance were sustained over time; their associations with child reports were predominantly small to moderate. These data suggest that clinician-reported LPPS ratings by themselves are inadequate for determining clinical trial eligibility and should be supplemented by appropriate measures of a child's functional status reflecting the child and caregiver perspectives.
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http://dx.doi.org/10.1002/cncr.33740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419065PMC
October 2021

Association of Medicaid Expansion with Cancer Stage and Disparities in Newly Diagnosed Young Adults.

J Natl Cancer Inst 2021 May 21. Epub 2021 May 21.

Surveillance and Health Services Research, American Cancer Society, Atlanta, GA, USA.

Background: Young adults (YAs) experience higher uninsurance rates and more advanced stage at cancer diagnosis than older counterparts. We examined the association of the Affordable Care Act Medicaid expansion with insurance coverage and stage at diagnosis among YAs newly diagnosed with cancer.

Methods: Using the National Cancer Database, we identified 309,413 YAs aged 18-39 years who received a first cancer diagnosis in 2011-2016. Outcomes included percentages of YAs without health insurance at diagnosis, with stage I (early-stage) diagnoses, and with stage IV (advanced-stage) diagnoses. We conducted difference-in-difference (DD) analyses to examine outcomes, before and after states implemented Medicaid expansion compared with non-expansion states. All statistical tests were 2-sided.

Results: The percentage of uninsured YAs decreased more in expansion than non-expansion states (adjusted DD = -1.0 percentage points [ppt]; 95% Confidence Interval [CI] = -1.4 to -0.7 ppt; p<0.001). The overall percentage of stage I diagnoses increased (adjusted DD = 1.4 ppt; 95% CI = 0.6 to 2.2 ppt; p<0.001) in expansion compared with non-expansion states, with greater improvement among YAs in rural areas (adjusted DD = 7.2 ppt; 95% CI = 0.2 to 14.3 ppt; p=0.045) than metropolitan areas (adjusted DD = 1.3 ppt; 95% CI = 0.4 to 2.2 ppt; p=0.004), and among non-Hispanic Black patients (adjusted DD = 2.2 ppt; 95% CI = -0.03 to 4.4 ppt; p=0.05) than non-Hispanic White patients (adjusted DD = 1.4 ppt; 95% CI = 0.4 to 2.3 ppt; p=0.008). Despite the non-statistically significant change in stage IV diagnoses overall, the percentage declined more (adjusted DD = -1.2 ppt; 95% CI = -2.2 to -0.2 ppt; p=0.02) among melanoma patients in expansion relative to non-expansion states.

Conclusions: We provide the first evidence on the association of Medicaid expansion with shifts to early-stage cancer at diagnosis and a narrowing of rural-urban and Black-White disparities in YA cancer patients.
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http://dx.doi.org/10.1093/jnci/djab105DOI Listing
May 2021

Patterns of surveillance for late effects of BCR-ABL tyrosine kinase inhibitors in survivors of pediatric Philadelphia chromosome positive leukemias.

BMC Cancer 2021 Apr 29;21(1):474. Epub 2021 Apr 29.

Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, Emory University, Atlanta, GA, USA.

Background: Targeted anticancer therapies such as BCR-ABL tyrosine kinase inhibitors (TKIs) have improved outcomes for chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, little is known about long-term risks of TKIs in children. Exposure-based survivorship guidelines do not include TKIs, thus surveillance practices may be variable.

Methods: We retrospectively examined surveillance for cardiac and endocrine late effects in children receiving TKIs for Ph + leukemias, diagnosed at < 21 years between 2000 and 2018. Frequency of echocardiogram (ECHO), electrocardiogram (EKG), thyroid stimulating hormone (TSH), dual-energy x-ray absorptiometry (DXA), and bone age testing were abstracted. Descriptive statistics were stratified by leukemia type.

Results: 66 patients (CML n = 44; Ph + ALL n = 22) met inclusion criteria. Among patients with CML, ≥1 evaluation was done: ECHO (50.0%), EKG (48.8%), TSH (43.9%), DXA (2.6%), bone age (7.4%). Among patients with Ph + ALL, ≥1 evaluation was done: ECHO (86.4%), EKG (68.2%), TSH (59.1%), DXA (63.6%), bone age (44.4%). Over a median 6.3 and 5.7 years of observation, respectively, 2% of patients with CML and 57% with Ph + ALL attended a survivorship clinic.

Conclusions: Despite common exposure to TKIs in survivors of Ph + leukemias, patterns of surveillance for late effects differed in CML and Ph + ALL, with the latter receiving more surveillance likely due to concomitant chemotherapy exposures. Targeted therapies such as TKIs are revolutionizing cancer treatment, but surveillance for late effects and referral to survivorship clinics are variable despite the chronicity of exposure. Evidence based guidelines and longer follow-up are needed.
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http://dx.doi.org/10.1186/s12885-021-08182-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082962PMC
April 2021

Evaluating palliative opportunities in pediatric patients with leukemia and lymphoma.

Cancer Med 2021 04 22;10(8):2714-2722. Epub 2021 Mar 22.

Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Atlanta, GA, USA.

Background: Despite favorable prognoses, pediatric patients with hematologic malignancies experience significant challenges that may lead to diminished quality of life or family stress. They are less likely to receive subspecialty palliative care (PC) consultation and often undergo intensive end-of-life (EOL) care. We examined "palliative opportunities," or events when the integration of PC would have the greatest impact, present during a patient's hematologic malignancy course and relevant associations.

Methods: A single-center retrospective review was conducted on patients aged 0-18 years with a hematologic malignancy who died between 1/1/12 and 11/30/17. Demographic, disease, and treatment data were collected. A priori, nine palliative opportunity categories were defined. Descriptive statistics were performed. Palliative opportunities were evaluated over temporal quartiles from diagnosis to death. Timing and rationale of pediatric PC consultation were evaluated.

Results: Patients (n = 92) had a median of 5.0 (interquartile range [IQR] 6.0) palliative opportunities, incurring 522 total opportunities, increasing toward the EOL. Number and type of opportunities did not differ by demographics. PC consultation was most common in patients with lymphoid leukemia (50.9%, 28/55) and myeloid leukemia (48.5%, 16/33) versus lymphoma (0%, 0/4, p = 0.14). Forty-four of ninety-two patients (47.8%) received PC consultation a median of 1.8 months (IQR 4.1) prior to death. Receipt of PC was associated with transplant status (p = 0.0018) and a higher number of prior palliative opportunities (p = 0.0005); 70.3% (367/522) of palliative opportunities occurred without PC.

Conclusion: Patients with hematologic malignancies experience many opportunities warranting PC support. Identifying opportunities for ideal timing of PC involvement may benefit patients with hematologic cancers and their caregivers.
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http://dx.doi.org/10.1002/cam4.3862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026931PMC
April 2021

Impact of Risk-Adapted Therapy for Pediatric Hodgkin Lymphoma on Risk of Long-Term Morbidity: A Report From the Childhood Cancer Survivor Study.

J Clin Oncol 2021 Jul 25;39(20):2266-2275. Epub 2021 Feb 25.

St Jude Children's Research Hospital, Memphis, TN.

Purpose: To determine the incidence of serious chronic health conditions among survivors of pediatric Hodgkin lymphoma (HL), compare by era of therapy and by selected cancer therapies, and provide estimates of risks associated with contemporary therapy.

Methods: Assessing 2,996 5-year HL survivors in the Childhood Cancer Survivor Study diagnosed from 1970 to 1999, we examined the cumulative incidence of severe to fatal chronic conditions (grades 3-5) using self-report conditions, medically confirmed subsequent malignant neoplasms, and cause of death based on the National Death Index. We used multivariable regression models to estimate hazard ratios (HRs) per decade and by key treatment exposures.

Results: HL survivors were of a mean age of 35.6 years (range, 12-58 years). The cumulative incidence of any grade 3-5 condition by 35 years of age was 31.4% (95% CI, 29.2 to 33.5). Females were twice as likely (HR, 2.1; 95% CI, 1.8 to 2.4) to have a grade 3-5 condition compared with males. From the 1970s to the 1990s, there was a 20% reduction (HR, 0.8; 95% CI, 0.7 to 0.9) in decade-specific risk of a grade 3-5 condition ( trend = .002). In survivors who had a recurrence and/or hematopoietic cell transplant, the risk of a grade 3-5 condition was substantially elevated, similar to that of survivors treated with high-dose, extended-field radiotherapy (HR, 1.2; 95% CI, 0.9 to 1.5). Compared with survivors treated with chest radiotherapy ≥ 35 Gy in combination with an anthracycline or alkylator, a contemporary regimen for low-intermediate risk HL was estimated to lead to a 40% reduction in risk of a grade 3-5 condition (HR, 0.6; 95% CI, 0.4 to 0.8).

Conclusion: This study demonstrates that risk-adapted therapy for pediatric HL has resulted in a significant reduction in serious long-term outcomes.
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http://dx.doi.org/10.1200/JCO.20.01186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260906PMC
July 2021

Quantifying the difference in risk of adverse events by induction treatment regimen in pediatric acute lymphoblastic leukemia.

Leuk Lymphoma 2021 04 1;62(4):899-908. Epub 2020 Dec 1.

Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.

The differences in overall morbidity by induction treatment regimen for pediatric acute lymphoblastic leukemia (ALL) are unknown. We examined a cohort of children with ALL who received induction chemotherapy between January 2010 and May 2018. We evaluated 20 clinically relevant adverse events (AEs) and readmission and ICU admission rates. Outcomes were compared between standard 3- and 4-drug treatment regimens in multivariate analyses using Cox proportional hazard ratios. Among 486 eligible patients, the risks of sepsis (HR = 2.16, 95% CI = 1.11-4.19), hypoxia (HR = 2.08, 95% CI = 1.03-4.18), hyperbilirubinemia (HR = 2.48, 95% CI = 1.07-5.74), hyperglycemia (HR = 2.65, 95% CI = 1.29-5.42), thromboembolic event (HR = 4.50, 95% CI = 1.30-15.6), and hyponatremia (HR = 7.88, 95% CI = 1.26-49.4) were significantly higher during 4-drug induction. Despite no differences in readmission or ICU admission rates, 4-drug induction patients had greater total inpatient days (12 vs. 4 days; <.0001). In conclusion, pediatric patients receiving 4-drug induction for ALL experience higher morbidity. These results inform care practices and patient guidance during induction therapy.
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http://dx.doi.org/10.1080/10428194.2020.1852471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012228PMC
April 2021

Melphalan induces cardiotoxicity through oxidative stress in cardiomyocytes derived from human induced pluripotent stem cells.

Stem Cell Res Ther 2020 11 5;11(1):470. Epub 2020 Nov 5.

Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, 2015 Uppergate Drive, Atlanta, GA, 30322, USA.

Background: Treatment-induced cardiotoxicity is a leading noncancer-related cause of acute and late onset morbidity and mortality in cancer patients on antineoplastic drugs such as melphalan-increasing clinical case reports have documented that it could induce cardiotoxicity including severe arrhythmias and heart failure. As the mechanism by which melphalan impairs cardiac cells remains poorly understood, here, we aimed to use cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) to investigate the cellular and molecular mechanisms of melphalan-induced cardiotoxicity.

Methods: hiPSC-CMs were generated and treated with clinically relevant doses of melphalan. To characterize melphalan-induced cardiotoxicity, cell viability and apoptosis were quantified at various treatment durations. Ca transient and contractility analyses were used to examine the alterations of hiPSC-CM function. Proteomic analysis, reactive oxygen species detection, and RNA-Sequencing were conducted to investigate underlying mechanisms.

Results: Melphalan treatment of hiPSC-CMs induced oxidative stress, caused Ca handling defects and dysfunctional contractility, altered global transcriptomic and proteomic profiles, and resulted in apoptosis and cell death. The antioxidant N-acetyl-L-cysteine attenuated these genomic, cellular, and functional alterations. In addition, several other signaling pathways including the p53 and transforming growth factor-β signaling pathways were also implicated in melphalan-induced cardiotoxicity according to the proteomic and transcriptomic analyses.

Conclusions: Melphalan induces cardiotoxicity through the oxidative stress pathway. This study provides a unique resource of the global transcriptomic and proteomic datasets for melphalan-induced cardiotoxicity and can potentially open up new clinical mechanism-based targets to prevent and treat melphalan-induced cardiotoxicity.
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http://dx.doi.org/10.1186/s13287-020-01984-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643439PMC
November 2020

Renal and Hepatic Health After Childhood Cancer.

Pediatr Clin North Am 2020 12 23;67(6):1203-1217. Epub 2020 Sep 23.

Department of Pediatrics, Hematology-Oncology, Emory University School of Medicine, Atlanta, GA, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.

Childhood cancer survivors (CCSs) are at risk for renal and hepatic complications related to curative cancer treatments. Although acute renal and hepatic toxicities of cancer treatments are well described, data regarding long-term and late-occurring sequelae or their associations with acute sequelae are less robust. This article highlights the literature on the prevalence of and risk factors for late renal and hepatic toxicity in CCSs. Studies investigating these outcomes are needed to inform surveillance practices and the development of future frontline cancer treatment protocols.
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http://dx.doi.org/10.1016/j.pcl.2020.07.011DOI Listing
December 2020

A strategy to reduce cumulative anthracycline exposure in low-risk pediatric acute myeloid leukemia while maintaining favorable outcomes.

Leuk Res 2020 09 12;96:106421. Epub 2020 Jul 12.

Department of Pediatrics, Emory University, Atlanta, GA, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.

Background: Advances in risk stratification have improved the 3-year disease-free survival (DFS) and overall survival (OS) of low-risk pediatric acute myeloid leukemia (LR-AML) to approximately 70 % and 85 % respectively. LR-AML is defined by favorable cytogenetic/molecular features and/or optimal early response to therapy. However, cumulative anthracycline exposure in contemporary Children's Oncology Group (COG) regimens approach a doxorubicin equivalent exposure of 540 mg/m; with rates of non-infection related left ventricular systolic dysfunction (LVSD) approaching 15 %. This is a major cause of toxicity in these patients and precludes the further use of anthracyclines in the relapsed setting; therefore, strategies that reduce cardiotoxicity while maintaining excellent outcomes are needed.

Patients And Methods: Twenty-seven pediatric patients with LR-AML were treated with an anthracycline-reduced approach (Aflac-AML regimen) between 2011 and 2016. Patients received four courses of therapy including three high-dose cytarabine containing courses and a cumulative doxorubicin equivalent exposure of 390 mg/m, a 28 % reduction in anthracycline dosing compared to current COG regimens.

Results: The 3-year DFS and OS was 70.0 % and 85.5 % respectively, from end of Induction I (first chemotherapy cycle) with a median follow-up of 3.2 years. These survival outcomes are comparable to current LR-AML regimens. Only two patients developed non-infection related LVSD during therapy and more importantly, none developed LVSD after completion of therapy.

Conclusion: These findings suggest that LR-AML outcomes can be maintained using a reduced anthracycline chemotherapy regimen, resulting in lower cardiac toxicity. This new chemotherapy backbone is now being tested prospectively (NCT04326439) to further validate its use in pediatric LR-AML.
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http://dx.doi.org/10.1016/j.leukres.2020.106421DOI Listing
September 2020

Association of GSTM1 null variant with anthracycline-related cardiomyopathy after childhood cancer-A Children's Oncology Group ALTE03N1 report.

Cancer 2020 09 15;126(17):4051-4058. Epub 2020 May 15.

Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Background: Anthracycline-related cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Glutathione S-transferases (GSTs) are a class of phase II detoxification enzymes that facilitate the elimination of anthracyclines. As free-radical scavengers, GSTs could play a role in oxidative damage-induced cardiomyopathy. Associations between the GSTμ1 (GSTM1) null genotype and iron-overload-related cardiomyopathy have been reported in patients with thalassemia.

Methods: The authors sought to identify an association between the GSTM1 null genotype and anthracycline-related cardiomyopathy in childhood cancer survivors and to corroborate the association by examining GSTM1 gene expression in peripheral blood and human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from survivors with and without cardiomyopathy. GSTM1 gene deletion was examined by polymerase chain reaction in 75 survivors who had clinically validated cardiomyopathy (cases) and in 92 matched survivors without cardiomyopathy (controls). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, chest radiation, and anthracycline dose was used to assess the association between genotype and cardiomyopathy. Proprietary bead array technology and quantitative real-time polymerase chain reaction were used to measure GSTM1 expression levels in samples from 20 cases and 20 matched controls. hiPSC-CMs from childhood cancer survivors (3 with cardiomyopathy, 3 without cardiomyopathy) also were examined for GSTM1 gene expression levels.

Results: A significant association was observed between the risk of cardiomyopathy and the GSTM1 null genotype (odds ratio, 2.7; 95% CI, 1.3-5.9; P = .007). There was significant downregulation of GSTM1 expression in cases compared with controls (average relative expression, 0.67 ± 0.57 vs 1.33 ± 1.33, respectively; P = .049). hiPSC-CMs from patients who had cardiomyopathy revealed reduced GSTM1 expression (P = .007).

Conclusions: The current findings could facilitate the identification of childhood cancer survivors who are at risk for anthracycline-related cardiomyopathy.
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http://dx.doi.org/10.1002/cncr.32948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423633PMC
September 2020

Validity and Reliability of the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events.

J Natl Cancer Inst 2020 11;112(11):1143-1152

Children's National Hospital, 111 Michigan Ave., N.W., Washington, DC 20010, USA.

Background: Patient-reported outcome (PRO) measurements linked to Common Terminology Criteria for Adverse Events (CTCAE) grading may improve symptom adverse event (AE) reporting in pediatric oncology trials. We evaluated construct validity, responsiveness, and test-retest reliability of the Ped-PRO-CTCAE measurement system for children and adolescents undergoing cancer care.

Methods: A total of 482 children and adolescents (7-18 years, 41.5% not non-Hispanic white) newly diagnosed with cancer and their caregivers participated from nine pediatric oncology hospitals. Surveys were completed at 72 hours preceding treatment initiation (T1) and at follow-up (T2) approximately 7-17 days later for chemotherapy, and 4+ weeks for radiation. Psychometric analyses examined the relationship of Ped-PRO-CTCAE items (assessing 62 symptom AEs) with Patient-Reported Outcomes Measurement Information System, Memorial Symptom Assessment Scale, Lansky Play-Performance Scale, and medication use. A separate test-retest study included 46 children.

Results: Ped-PRO-CTCAE and Memorial Symptom Assessment Scale were strongly correlated across age groups at T2: 7-12 years (r = 0.62-0.80), 13-15 years (r = 0.44-0.94), and 16-18 years (r = 0.65-0.98); and over time. The Ped-PRO-CTCAE was strongly correlated with Patient-Reported Outcomes Measurement Information System Pediatric measures at T2; for example, pain interference (r = 0.70, 95% confidence interval [CI] = 0.64 to 0.76), fatigue severity (r = 0.63, 95% CI = 0.56 to 0.69), and depression severity (r = 0.76, 95% CI = 0.71 to 0.81). Ped-PRO-CTCAE items differentiated children by Lansky Play-Performance Scale and by medication use. Test-retest agreement ranged from 54.3% to 93.5%.

Conclusions: This longitudinal study provided evidence for the construct validity and reliability of the core Ped-PRO-CTCAE symptom AE items relative to several established measures. Additional responsiveness data with clinical anchors are recommended. Incorporation of Ped-PRO-CTCAE in trials may lead to a better understanding of the cancer treatment experience.
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http://dx.doi.org/10.1093/jnci/djaa016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669229PMC
November 2020

Closing the survivorship gap in children and adolescents with Hodgkin lymphoma.

Br J Haematol 2019 12 30;187(5):573-587. Epub 2019 Sep 30.

Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

The treatment of Hodgkin lymphoma (HL) is one of early success. However, disease-free survival (DFS) does not reflect latent organ injury and its impact on health status and well-being beyond 5 years. In fact, we are at a crossroads, in terms of needing individualized approaches to maintain DFS, while minimizing late effects and preserving health-related quality of life (HRQoL). Premature morbidity and mortality translate to a high societal cost associated with the potential number of productive life years ahead in this population who are young at diagnosis. The discordance between short-term lymphoma-free survival and long-term health and HRQoL creates a "survivorship gap" which can be characterized for individuals and for subgroups of patients. The current review delineates contributors to compromised outcomes and health status in child and adolescent (paediatric) HL and frames the survivorship gap in terms of primary and secondary prevention. Primary prevention aims to titrate therapy. Secondary prevention entails strategies to intervene against late effects. Bridging the survivorship gap will be attained with enhanced knowledge of and attention to biology of the tumour and microenvironment, host genetic factors, HRQoL and sub-populations with disparate outcomes.
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http://dx.doi.org/10.1111/bjh.16197DOI Listing
December 2019

Mapping child and adolescent self-reported symptom data to clinician-reported adverse event grading to improve pediatric oncology care and research.

Cancer 2020 01 25;126(1):140-147. Epub 2019 Sep 25.

Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina.

Background: Clinicians are the standard source for adverse event (AE) reporting in oncology trials, despite the subjective nature of symptomatic AEs. The authors designed a pediatric patient-reported outcome (PRO) instrument for symptomatic AEs to support the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) (the Pediatric PRO-CTCAE). The current study developed a standardized algorithm that maps all possible Pediatric PRO-CTCAE response patterns to recommended CTCAE grades to improve the accuracy of AE reporting in pediatric oncology trials.

Methods: Two rounds of surveys were administered to experienced cancer clinicians across 9 pediatric hospitals. In round 1, pediatric oncologists assigned CTCAE grades to all 101 possible Pediatric PRO-CTCAE response patterns. The authors evaluated clinician agreement of CTCAE grades across response patterns and categorized each response pattern as having high or low agreement. In round 2, a survey was sent to a larger clinician group to examine clinician agreement among a select set of Pediatric PRO-CTCAE response patterns, and the authors examined how clinical context influenced grade assignment.

Results: A total of 10 pediatric oncologists participated in round 1. Of the 101 possible patterns, 89 (88%) had high agreement. The Light weighted kappa was averaged across the 10 oncologists (Light kappa = 0.73; 95% CI, 0.66-0.81). A total of 139 clinicians participated in round 2. High clinician agreement remained for the majority of generic response patterns and the clinical context did not typically change grades but rather improved agreement.

Conclusions: The current study provides a framework for integrating child self-reported symptom data directly into mandated AE reporting in oncology trials. Translating Pediatric PRO-CTCAE responses into clinically meaningful metrics will guide future cancer care and toxicity grading.
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http://dx.doi.org/10.1002/cncr.32525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906242PMC
January 2020

Survival by Race and Ethnicity in Pediatric and Adolescent Patients With Hodgkin Lymphoma: A Children's Oncology Group Study.

J Clin Oncol 2019 11 20;37(32):3009-3017. Epub 2019 Sep 20.

Emory University School of Medicine, Atlanta, GA.

Purpose: Population-based studies of children and adolescents with Hodgkin lymphoma (HL) report a survival disadvantage in nonwhite-non-Hispanic black (NHB) and Hispanic-patients. Whether disparities persist after adjustment for clinical and treatment-related variables is unknown. We examined survival by race/ethnicity in children receiving risk-based, response-adapted, combined-modality therapy for HL in contemporary Children's Oncology Group trials.

Patients And Methods: This pooled analysis used individual-level data from 1,605 patients (younger than age 1 to 21 years) enrolled in phase III trials for low-risk (AHOD0431), intermediate-risk (AHOD0031), and high-risk (AHOD0831) HL from 2002 to 2012. Event-free survival (EFS) and overall survival (OS) were compared between non-Hispanic white (NHW) and nonwhite patients. Cox proportional hazards for survival were estimated for both de novo and relapsed HL, adjusting for demographics, disease characteristics, and therapy.

Results: At median follow up of 6.9 years, cumulative incidence of relapse was 17%. Unadjusted 5-year EFS and OS were 83% (SE, 1.2%) and 97% (SE, < 1%), respectively. Neither differed by race/ethnicity. In multivariable analyses for OS, nonwhite patients had a 1.88× higher hazard of death (95% CI, 1.1 to 3.3). Five-year postrelapse survival probabilities by race were as follows: NHW, 90%; NHB, 66%; and Hispanic, 80% ( < .01). Compared with NHW, Hispanic and NHB children had 2.7-fold (95% CI, 1.2 to 6.2) and 3.5-fold (95% CI, 1.5 to 8.2) higher hazard of postrelapse mortality, respectively.

Conclusion: In patients who were treated for de novo HL in contemporary Children's Oncology Group trials, EFS did not differ by race/ethnicity; however, adjusted OS was significantly worse in nonwhite patients, a finding driven by increased postrelapse mortality in this population. Additional studies examining treatment and survival disparities after relapse are warranted.
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http://dx.doi.org/10.1200/JCO.19.00812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839907PMC
November 2019

Suboptimal uptake of human papillomavirus (HPV) vaccine in survivors of childhood and adolescent and young adult (AYA) cancer.

J Cancer Surviv 2019 Oct 24;13(5):730-738. Epub 2019 Jul 24.

Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Purpose: To estimate the population-based incidence of HPV vaccination after childhood cancer.

Methods: Pediatric and young adult cancer survivors identified in the institutional Comprehensive Cancer Center registry were linked to the North Carolina Immunization Registry (NCIR). Initiation and completion of any HPV vaccine was evaluated in survivors born between 1984 and 2002 with an NCIR record by December 2014. Descriptive statistics and Kaplan-Meier estimates of cumulative incidence were stratified by sex and age at eligibility for vaccine. Cox proportional hazards were conducted and stratified by sex.

Results: Among 879 (n = 428 female; n = 451 male) study-eligible cancer survivors without prior HPV vaccination (n = 501 < 18 years, n = 378 ≥ 18 years at the time of eligibility), the cumulative incidence of HPV vaccine initiation following cancer therapy was 48.1% among females at 8.2 years and 29.2% among males at 5.0 years after vaccine eligibility among those < 18 years, and 6.2% among females at 8.1 years and 2.0% among males at 4.2 years after vaccine eligibility among those ≥ 18 years. Among those who initiated vaccination, 53% of females and 43% of males completed a 3-dose series. Younger age at cancer diagnosis (≤ 10 and 11-14 years vs. ≥ 15 years) and shorter interval from diagnosis to vaccine eligibility were more likely to initiate vaccination in models adjusted for age at eligibility, race/ethnicity, cancer type, relapse, and transplant.

Conclusions: Despite the benefit of a cancer prevention strategy, cancer survivors are sub-optimally vaccinated against HPV.

Implications For Cancer Survivors: Immunization registries can help oncologists and primary care providers identify gaps in vaccination and target HPV vaccine delivery in survivors.
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http://dx.doi.org/10.1007/s11764-019-00791-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832771PMC
October 2019

Intent and subsequent initiation of human papillomavirus vaccine among young cancer survivors.

Cancer 2019 11 10;125(21):3810-3817. Epub 2019 Jul 10.

School of Nursing, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Despite an increased risk of subsequent human papillomavirus (HPV)-related malignancies, HPV vaccine initiation rates among cancer survivors remain critically low. The purpose of this study was to determine the relationship between HPV vaccine intent and subsequent vaccine initiation among cancer survivors by linking data from a cross-sectional survey with state-based immunization registry records.

Methods: Cancer survivors who were 9 to 26 years old were surveyed 1 to 5 years after their treatment to assess their HPV vaccine initiation status, HPV vaccine intent, sociodemographic factors, and vaccine-related health beliefs. HPV vaccine doses/dates were abstracted from the Georgia Registry for Immunization Transactions for 3.5 years after survey participation. Logistic regression models identified factors associated with vaccine intent and subsequent vaccine initiation.

Results: Among survivors who were HPV vaccine-naive at survey participation (n = 103), factors associated with vaccine intent included the following: 1) provider recommendation for the HPV vaccine (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.4-18.1; P = .014), 2) positive general attitude toward vaccines (OR, 4.8; 95% CI, 2.0-11.2; P < .001), and 3) perceived severity of HPV disease (OR, 3.5; 95% CI, 1.2-9.9; P = .02). Of the vaccine-naive patients, 28 initiated the HPV vaccine at a median of 1.1 years after the survey. Initiation was more likely among survivors who had reported vaccine intent (OR, 3.9; 95% CI, 1.2-12.5; P = .02) and was less likely among older survivors (OR per year, 0.7; 95% CI, 0.6-0.9; P < .001).

Conclusions: These findings suggest that provider recommendation for the HPV vaccine plays a role in establishing intent, which then translates into subsequent initiation.
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http://dx.doi.org/10.1002/cncr.32379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427343PMC
November 2019

Hepatic late adverse effects after antineoplastic treatment for childhood cancer.

Cochrane Database Syst Rev 2019 04 15;4:CD008205. Epub 2019 Apr 15.

Department of Paediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, PO Box 22660, Amsterdam, Netherlands, 1100 DD.

Background: Survival rates have greatly improved as a result of more effective treatments for childhood cancer. Unfortunately, the improved prognosis has been accompanied by the occurrence of late, treatment-related complications. Liver complications are common during and soon after treatment for childhood cancer. However, among long-term childhood cancer survivors, the risk of hepatic late adverse effects is largely unknown. To make informed decisions about future cancer treatment and follow-up policies, it is important to know the risk of, and associated risk factors for, hepatic late adverse effects. This review is an update of a previously published Cochrane review.

Objectives: To evaluate all the existing evidence on the association between antineoplastic treatment (that is, chemotherapy, radiotherapy involving the liver, surgery involving the liver and BMT) for childhood cancer and hepatic late adverse effects.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2018, Issue 1), MEDLINE (1966 to January 2018) and Embase (1980 to January 2018). In addition, we searched reference lists of relevant articles and scanned the conference proceedings of the International Society of Paediatric Oncology (SIOP) (from 2005 to 2017) and American Society of Pediatric Hematology/Oncology (ASPHO) (from 2013 to 2018) electronically.

Selection Criteria: All studies, except case reports, case series, and studies including fewer than 10 patients that examined the association between antineoplastic treatment for childhood cancer (aged 18 years or less at diagnosis) and hepatic late adverse effects (one year or more after the end of treatment).

Data Collection And Analysis: Two review authors independently performed the study selection and 'risk of bias' assessment. The 'risk of bias' assessment was based on earlier checklists for observational studies. For the original version of the review, two review authors independently performed data extraction. For the update of the review, the data extraction was performed by one reviewer and checked by another reviewer.

Main Results: Thirteen new studies were identified for the update of this review. In total, we included 33 cohort studies including 7876 participants investigating hepatic late adverse effects after antineoplastic treatment (especially chemotherapy and radiotherapy) for different types of childhood cancer, both haematological and solid malignancies. All studies had methodological limitations. The prevalence of hepatic late adverse effects, all defined in a biochemical way, varied widely, between 0% and 84.2%. Selecting studies where the outcome of hepatic late adverse effects was well-defined as alanine aminotransferase (ALT) above the upper limit of normal, indicating cellular liver injury, resulted in eight studies. In this subgroup, the prevalence of hepatic late adverse effects ranged from 5.8% to 52.8%, with median follow-up durations varying from three to 23 years since cancer diagnosis in studies that reported the median follow-up duration. A more stringent selection process using the outcome definition of ALT as above twice the upper limit of normal, resulted in five studies, with a prevalence ranging from 0.9% to 44.8%. One study investigated biliary tract injury, defined as gamma-glutamyltransferase (γGT) above the upper limit of normal and above twice the upper limit of normal and reported a prevalence of 5.3% and 0.9%, respectively. Three studies investigated disturbance in biliary function, defined as bilirubin above the upper limit of normal and reported prevalences ranging from 0% to 8.7%. Two studies showed that treatment with radiotherapy involving the liver (especially after a high percentage of the liver irradiated), higher BMI, and longer follow-up time or older age at evaluation increased the risk of cellular liver injury in multivariable analyses. In addition, there was some suggestion that busulfan, thioguanine, hepatic surgery, chronic viral hepatitis C, metabolic syndrome, use of statins, non-Hispanic white ethnicity, and higher alcohol intake (> 14 units per week) increase the risk of cellular liver injury in multivariable analyses. Chronic viral hepatitis was shown to increase the risk of cellular liver injury in six univariable analyses as well. Moreover, one study showed that treatment with radiotherapy involving the liver, higher BMI, higher alcohol intake (> 14 units per week), longer follow-up time, and older age at cancer diagnosis increased the risk of biliary tract injury in a multivariable analysis.

Authors' Conclusions: The prevalence of hepatic late adverse effects among studies with an adequate outcome definition varied considerably from 1% to 53%. Evidence suggests that radiotherapy involving the liver, higher BMI, chronic viral hepatitis and longer follow-up time or older age at follow-up increase the risk of hepatic late adverse effects. In addition, there may be a suggestion that busulfan, thioguanine, hepatic surgery, higher alcohol intake (>14 units per week), metabolic syndrome, use of statins, non-Hispanic white ethnicity, and older age at cancer diagnosis increase the risk of hepatic late adverse effects. High-quality studies are needed to evaluate the effects of different therapy doses, time trends, and associated risk factors after antineoplastic treatment for childhood cancer.
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http://dx.doi.org/10.1002/14651858.CD008205.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463806PMC
April 2019

Cost, Value, and Financial Hardship in Cancer Care: Implications for Pediatric Oncology.

Am Soc Clin Oncol Educ Book 2018 May;38:850-860

From Tufts Medical Center, Boston, MA; Children's Hospital of Atlanta/Emory University, Atlanta, GA; American Cancer Society, Atlanta, GA.

Cancer care in the United States faces a perfect storm: an aging population and expected increased cancer incidence, growing numbers of cancer survivors with ongoing care needs, and continued scientific advancements, offering extraordinary promise at extraordinary cost. How, then, do we as pediatric oncologists engage in the dialogue about cancer cost considerations? The purpose of this article and its accompanying session presented at the 2018 ASCO Annual Meeting is to introduce concepts of cost, value, and financial hardship. In the first section, we will provide an overview of principles of health economics, including components of cost, time horizon consideration, discounting, and methods to calculate incremental cost-effectiveness among therapeutic approaches. We will then introduce the value framework being debated in adult oncology and offer potential opportunities for its application in pediatric oncology. In the second section, we will describe the integration of the cost-effectiveness paradigm in an ongoing pediatric clinical trial, including design and analytic considerations. In the third section, we will shift away from cost to the health care system to cost to the patient, which is also termed "financial toxicity" or "financial hardship," focusing on the ongoing burden of cost on survivors of childhood cancer. Our goal is to provide our readers with the vocabulary and understanding of this complex and often thorny debate so that they can be active participants and informed advocates for their patients.
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http://dx.doi.org/10.1200/EDBK_200359DOI Listing
May 2018

Left Ventricular Mass Change After Anthracycline Chemotherapy.

Circ Heart Fail 2018 07;11(7):e004560

Sections on Cardiovascular Medicine (J.H.J., G.C.M., S.V., D.W.K., W.O.N., W.G.H.)

Background: Myocardial atrophy and left ventricular (LV) mass reductions are associated with fatigue and exercise intolerance. The relationships between the receipt of anthracycline-based chemotherapy (Anth-bC) and changes in LV mass and heart failure (HF) symptomatology are unknown, as is their relationship to LV ejection fraction (LVEF), a widely used measurement performed in surveillance strategies designed to avert symptomatic HF associated with cancer treatment.

Methods And Results: We performed blinded, serial assessments of body weight, LVEF and mass, LV-arterial coupling, aortic stiffness, and Minnesota Living with Heart Failure Questionnaire measures before and 6 months after initiating Anth-bC (n=61) and non-Anth-bC (n=15), and in 24 cancer-free controls using paired and χ tests and multivariable linear models. Participants averaged 51±12 years, and 70% were women. Cancer diagnoses included breast cancer (53%), hematologic malignancy (42%), and soft tissue sarcoma (5%). We observed a 5% decline in both LVEF (<0.0001) and LV mass (=0.03) in the setting of increased aortic stiffness and disrupted ventricular-arterial coupling in those receiving Anth-bC but not other groups (=0.11-0.92). A worsening of the Minnesota Living with Heart Failure Questionnaire score in Anth-bC recipients was associated with myocardial mass declines (=-0.27; <0.01) but not with LVEF declines (=0.11; =0.45). Moreover, this finding was independent of LVEF changes and body weight.

Conclusions: Early after Anth-bC, LV mass reductions associate with worsening HF symptomatology independent of LVEF. These data suggest an alternative mechanism whereby anthracyclines may contribute to HF symptomatology and raise the possibility that surveillance strategies during Anth-bC should also assess LV mass.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.117.004560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729136PMC
July 2018

Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: A report from the Children's Oncology Group.

Cancer 2018 08 8;124(15):3210-3219. Epub 2018 May 8.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.

Background: The Children's Oncology Group AHOD0431 study evaluated a response-directed treatment paradigm in which minimal initial chemotherapy and low-dose radiation was received only by patients who did not achieve a complete remission, and a chemotherapy/low-dose radiation salvage regimen was received by those who had a protocol-defined, low-risk recurrence.

Methods: Patients younger than 21 years who had stage IA or IIA nonbulky disease were eligible. The treatment strategy was evaluated by determining the proportion that received minimal chemotherapy alone, the proportion that had a first or second remission without the receipt of high-dose chemotherapy/stem cell rescue or higher dose involved-field radiation therapy (>21 grays), and overall survival.

Results: In total, 278 patients were eligible. At 4 years, 49.0% had received minimal chemotherapy and no radiation, 88.8% were in remission without receiving high-dose chemotherapy with stem cell rescue or >21 grays of involved-field radiation therapy, and the overall survival rate was 99.6%. Patients who had mixed cellularity histology had a 4-year event-free survival (EFS) rate of 95.2%, which was significantly better than the 75.8% EFS for those who had nodular sclerosis histology (P = .008). A red blood cell sedimentation rate ≤20 mm/hour and a negative fluorodeoxyglucose-positron emission tomography scan after 1 cycle of chemotherapy (PET1) were associated with a favorable EFS outcome. The study was closed early when the receipt of radiation therapy exceeded the predefined monitoring boundary.

Conclusions: This limited chemotherapy response-based approach was successful in patients who had a negative PET1 result, had MC histology, or had a low red blood cell sedimentation rate. In this treatment paradigm, evaluation of increased chemotherapy intensity or the integration of active new agents is indicated for patients who have nodular sclerosis histology with a high ESR or who have a positive PET1 result. Cancer 2018. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097921PMC
August 2018

Early-stage Hodgkin lymphoma in the modern era: simulation modelling to delineate long-term patient outcomes.

Br J Haematol 2018 07 29;182(2):212-221. Epub 2018 Apr 29.

Division of Blood Disorders, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.

We developed a novel simulation model integrating multiple data sets to project long-term outcomes with contemporary therapy for early-stage Hodgkin lymphoma (ESHL), namely combined modality therapy (CMT) versus chemotherapy alone (CA) via F-fluorodeoxyglucose positron emission tomography response-adaption. The model incorporated 3-year progression-free survival (PFS), probability of cure with/without relapse, frequency of severe late effects (LEs), and 35-year probability of LEs. Furthermore, we generated estimates for quality-adjusted life years (QALYs) and unadjusted survival (life years, LY) and used model projections to compare outcomes for CMTversusCA for two index patients. Patient 1: a 25-year-old male with favourable ESHL (stage IA); Patient 2: a 25-year-old female with unfavourable ESHL (stage IIB). Sensitivity analyses assessed the impact of alternative assumptions for LE probabilities. For Patient 1, CMT was superior to CA (CMT incremental gain = 0·11 QALYs, 0·21 LYs). For Patient 2, CA was superior to CMT (CA incremental gain = 0·37 QALYs, 0·92 LYs). For Patient 1, the advantage of CMT changed minimally when the proportion of severe LEs was reduced from 20% to 5% (0·15 QALYs, 0·43 LYs), whereas increasing the severity proportion for Patient 2's LEs from 20% to 80% enhanced the advantage of CA (1·1 QALYs, 6·5 LYs). Collectively, this detailed simulation model quantified the long-term impact that varied host factors and alternative contemporary treatments have in ESHL.
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http://dx.doi.org/10.1111/bjh.15255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055753PMC
July 2018

Patterns and predictors of clustered risky health behaviors among adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Cancer 2016 09 3;122(17):2747-56. Epub 2016 Jun 3.

Epidemiology/Cancer Control Department, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Health complications related to childhood cancer may be influenced by risky health behaviors (RHBs), particularly when RHBs co-occur. To the authors' knowledge, only limited information is available describing how RHBs cluster among survivors of childhood cancer and their siblings and the risk factors for co-occurring RHBs.

Methods: Latent class analysis was used to identify RHB clusters using longitudinal survey data regarding smoking, alcohol use, and physical activity from adult survivors (4184 survivors) and siblings (1598 siblings) in the Childhood Cancer Survivor Study. Generalized logistic regression was used to evaluate associations between demographic characteristics, treatment exposures, psychological distress, health conditions, and cluster membership.

Results: Three RHB clusters were identified: a low-risk cluster, an insufficiently active cluster, and a high-risk cluster (tobacco and risky alcohol use and insufficient activity). Compared with siblings, survivors were more likely to be in the insufficiently active cluster (adjusted odds ratio [ORadj ], 1.17; 95% confidence interval [95% CI], 1.06-1.27) and were less likely to be in the high-risk cluster (ORadj , 0.79; 95% CI, 0.69-0.88). Risk factors for membership in the high-risk cluster included psychological distress (ORadj , 2.76; 95% CI, 1.98-3.86), low educational attainment (ORadj , 7.49; 95% CI, 5.15-10.88), income <$20,000 (ORadj , 2.62; 95% CI, 1.93-3.57), being divorced/separated or widowed (ORadj , 1.36; 95% CI, 1.03-1.79), and limb amputation (ORadj , 1.52; 95% CI, 1.03-2.24). Risk factors for the insufficiently active cluster included chronic health conditions, psychological distress, low education or income, being obese or overweight, female sex, nonwhite race/ethnicity, single marital status, cranial radiation, and cisplatin exposure.

Conclusions: RHBs co-occur in survivors of childhood cancer and their siblings. Economic and educational disadvantages and psychological distress should be considered in screening and interventions to reduce RHBs. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2747-2756. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992459PMC
September 2016

CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children's Oncology Group Genome-Wide Association Study.

J Clin Oncol 2016 Mar 25;34(8):863-70. Epub 2016 Jan 25.

Xuexia Wang, University of Wisconsin-Milwaukee, Milwaukee, WI; Can-Lan Sun, Molly Mather, Saro H. Armenian, City of Hope, Duarte; Jerome I. Rotter, Kent D. Taylor, Yii-Der Ida Chen, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles, Torrance, CA; Adolfo Quiñones-Lombraña, Javier G. Blanco, State University of New York at Buffalo, Buffalo; Kevin C. Oeffinger, Memorial Sloan Kettering Cancer Center, New York, NY; Purnima Singh, Wendy Landier, Lindsey Hageman, Smita Bhatia, University of Alabama at Birmingham, Birmingham, AL; Naomi Winick, University of Texas Southwestern Medical Center, Dallas; Zoann E. Dreyer, Texas Children's Cancer Center, Houston, TX; Jill P. Ginsberg, Childrens Hospital of Philadelphia, Philadelphia, PA; Joseph P. Neglia, University of Minnesota, Minneapolis, MN; Sharon M. Castellino, Emory University and Children's Healthcare of Atlanta, Atlanta, GA; and Melissa M. Hudson, Leslie L. Robison, St Jude Children's Research Hospital, Memphis, TN.

Purpose: Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests that genetic susceptibility could play a role. The current study uses an agnostic approach to identify genetic variants that could modify cardiomyopathy risk.

Methods: A genome-wide association study was conducted in childhood cancer survivors with and without cardiomyopathy (cases and controls, respectively). Single-nucleotide polymorphisms (SNPs) that surpassed a prespecified threshold for statistical significance were independently replicated. The possible mechanistic significance of validated SNP(s) was sought by using healthy heart samples.

Results: No SNP was marginally associated with cardiomyopathy. However, SNP rs1786814 on the CELF4 gene passed the significance cutoff for gene-environment interaction (Pge = 1.14 × 10(-5)). Multivariable analyses adjusted for age at cancer diagnosis, sex, anthracycline dose, and chest radiation revealed that, among patients with the A allele, cardiomyopathy was infrequent and not dose related. However, among those exposed to greater than 300 mg/m(2) of anthracyclines, the rs1786814 GG genotype conferred a 10.2-fold (95% CI, 3.8- to 27.3-fold; P < .001) increased risk of cardiomyopathy compared with those who had GA/AA genotypes and anthracycline exposure of 300 mg/m(2) or less. This gene-environment interaction was successfully replicated in an independent set of anthracycline-related cardiomyopathy. CUG-BP and ETR-3-like factor proteins control developmentally regulated splicing of TNNT2, the gene that encodes for cardiac troponin T (cTnT), a biomarker of myocardial injury. Coexistence of more than one cTnT variant results in a temporally split myofilament response to calcium, which causes decreased contractility. Analysis of TNNT2 splicing variants in healthy human hearts suggested an association between the rs1786814 GG genotype and coexistence of more than one TNNT2 splicing variant (90.5% GG v 41.7% GA/AA; P = .005).

Conclusion: We report a modifying effect of a polymorphism of CELF4 (rs1786814) on the dose-dependent association between anthracyclines and cardiomyopathy, which possibly occurs through a pathway that involves the expression of abnormally spliced TNNT2 variants.
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http://dx.doi.org/10.1200/JCO.2015.63.4550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070560PMC
March 2016
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