Publications by authors named "Paul C Nathan"

178 Publications

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 Feb 25:JCO2001186. 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
February 2021

Adolescents and young adult acute myeloid leukemia outcomes at pediatric versus adult centers: A population-based study.

Pediatr Blood Cancer 2021 Feb 8:e28939. Epub 2021 Feb 8.

Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.

Background: Adolescents and young adult (AYA) acute myeloid leukemia (AML) outcomes remain poor. The impact of locus of care (LOC; adult vs pediatric) in this population is unknown.

Procedure: The IMPACT cohort comprises detailed data for all Ontario, Canada, AYA aged 15-21 years diagnosed with AML between 1992 and 2012, linked to population-based health administrative data. We determined the impact of LOC on event-free survival (EFS) and overall survival (OS), treatment-related mortality (TRM), and relapse/progression.

Results: Among 140 AYA, 51 (36.4%) received therapy at pediatric centers. The five-year EFS and OS for the whole cohort were 35.0% ± 4.0% and 53.6% ± 4.2%. Cumulative doses of anthracycline were higher among pediatric center AYA [median 355 mg/m , interquartile range (IQR) 135-492 vs 202 mg/m , IQR 140-364; P = 0.003]. In multivariable analyses, LOC was not predictive of either EFS [adult vs pediatric center hazard ratio (HR) 1.3, 95% confidence interval (CI) 0.8-2.2, P = 0.27] or OS (HR 1.0, CI 0.6-1.6, P = 0.97). However, patterns of treatment failure varied; higher two-year incidence of TRM in pediatric centers (23.5% ± 6.0% vs.10.1% ± 3.2%; P = 0.046) was balanced by lower five-year incidence of relapse/progression (33.3% ± 6.7% vs 56.2% ± 5.3%; P = 0.002).

Conclusions: AYA AML survival outcomes did not vary between pediatric and adult settings. Causes of treatment failure were different, with higher intensity pediatric protocols associated with higher TRM but lower relapse/progression. Careful risk stratification and enhanced supportive care may be of substantial benefit to AYA with AML by allocating maximal treatment intensity to patients who most benefit while minimizing the risk of TRM.
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http://dx.doi.org/10.1002/pbc.28939DOI Listing
February 2021

Incidence and Predictors of Mental Health Outcomes Among Survivors of Adolescent and Young Adult Cancer: A Population-Based Study Using the IMPACT Cohort.

J Clin Oncol 2021 Jan 25:JCO2002019. Epub 2021 Jan 25.

Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Purpose: Risk and predictors of long-term mental health outcomes in survivors of adolescent and young adult (AYA) cancers are poorly characterized. Mental health is consequently neglected in long-term follow-up.

Methods: We identified all AYA in Ontario, Canada age 15-21 years when diagnosed with one of six common cancers between 1992-2012 using a population-based database, and compared them with matched controls. Linkage to provincial healthcare data allowed analysis of rates of outpatient (family physician and psychiatrist) visits for psychiatric indications and time to severe psychiatric events (emergency room visit, hospitalization, and suicide). Demographic-, disease-, and treatment-related predictors of adverse outcomes, including treatment setting (adult pediatric), were examined.

Results: Among 2,208 survivors and 10,457 matched controls, 5-year survivors experienced higher rates of outpatient mental health visits than controls (671 visits per 1,000 person-years 506; adjusted rate ratio [RR] 1.3; 95% CI, 1.1 to 1.5; = .006). Risk of a severe psychiatric episode was also increased among survivors (adjusted hazard ratio [HR], 1.2; 95% CI, 1.1 to 1.4, = .008). Risk of a psychotic disorder-associated severe event was doubled in survivors (HR, 2.0, 95% CI, 1.3 to 2.4; = .007) although absolute risk remained low (15-year cumulative incidence 1.7%; 95% CI, 1.0 to 2.7). In multivariable analysis, survivors treated in adult centers experienced substantially higher outpatient visit rates compared with those treated in pediatric settings (RR 1.8; 95% CI, 1.0 to 3.1; = .04).

Conclusion: Survivors of AYA cancer are at substantially increased risk of adverse mental health outcomes, with those treated in adult centers at particular risk. Although absolute incidence was low, survivors were at increased risk of psychotic disorder-associated severe events. Long-term mental health surveillance is warranted, as is research into effective interventions during or after cancer treatment.
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http://dx.doi.org/10.1200/JCO.20.02019DOI Listing
January 2021

Challenges associated with retrospective analysis of left ventricular function using clinical echocardiograms from a multicenter research study.

Echocardiography 2021 Feb 24;38(2):296-303. Epub 2021 Jan 24.

The Hospital for Sick Children, University of Toronto, Toronto, ON, USA.

Background: Retrospective multicenter research using echocardiograms obtained for routine clinical care can be hampered by issues of individual center quality. We sought to evaluate imaging and patient characteristics associated with poorer quality of archived echocardiograms from a cohort of childhood cancer survivors.

Methods: A single blinded reviewer at a central core laboratory graded quality of clinical echocardiograms from five centers focusing on images to derive 2D and M-mode fractional shortening (FS), biplane Simpson's ejection fraction (EF), myocardial performance index (MPI), tissue Doppler imaging (TDI)-derived velocities, and global longitudinal strain (GLS).

Results: Of 535 studies analyzed in 102 subjects from 2004 to 2017, all measures of cardiac function could be assessed in only 7%. While FS by 2D or M-mode, MPI, and septal E/E' could be measured in >80% studies, mitral E/E' was less consistent (69%), but better than EF (52%) and GLS (10%). 66% of studies had ≥1 issue, with technical issues (eg, lung artifact, poor endocardial definition) being the most common (33%). Lack of 2- and 3-chamber views was associated with the performing center. Patient age <5 years had a higher chance of apex cutoff in 4-chamber views compared with 16-35 years old. Overall, for any quality issue, earlier era of echo and center were the only significant risk factors.

Conclusion: Assessment of cardiac function using pooled multicenter archived echocardiograms was significantly limited. Efforts to standardize clinical echocardiographic protocols to include apical 2- and 3-chamber views and TDI will improve the ability to quantitate LV function.
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http://dx.doi.org/10.1111/echo.14983DOI Listing
February 2021

Expenditures among young adults with acute lymphoblastic leukemia by site of care.

Cancer 2021 Jan 19. Epub 2021 Jan 19.

Division of Pediatric Hematology-Oncology, Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Individuals diagnosed with acute lymphoblastic leukemia (ALL) between the ages of 22 and 39 years experience worse outcomes than those diagnosed when they are 21 years old or younger. Treatment at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) mitigates these disparities but may be associated with higher expenditures.

Methods: Using deidentified administrative claims data (OptumLabs Data Warehouse), the cancer-related expenditures were examined among patients with ALL diagnosed between 2001 and 2014. Multivariable generalized linear model with log-link modeled average monthly health-plan-paid (HPP) expenditures and amount owed by the patient (out-of-pocket [OOP]). Cost ratios were used to calculate excess expenditures (CCC vs non-CCC). Incidence rate ratios (IRRs) compared CCC and non-CCC monthly visit rates. Models adjusted for sociodemographics, comorbidities, adverse events, and months enrolled.

Results: Clinical and sociodemographic characteristics were comparable between CCC (n = 160) and non-CCC (n = 139) patients. Higher monthly outpatient expenditures in CCC patients ($15,792 vs $6404; P < .001) were driven by outpatient hospital HPP expenditures. Monthly visit rates and per visit expenditures for nonchemotherapy visits (IRR = 1.6; P = .001; CCC = $8247, non-CCC = $1191) drove higher outpatient hospital expenditures among CCCs. Monthly OOP expenditures were higher at CCCs for outpatient care (P = .02). Inpatient HPP expenditures were significantly higher at CCCs ($25,918 vs $13,881; ꞵ = 0.9; P < .001) before accounting for adverse events but were no longer significant after adjusting for adverse events (ꞵ = 0.4; P = .1). Hospitalizations and length of stay were comparable.

Conclusions: Young adults with ALL at CCCs have higher expenditures, likely reflecting differences in facility structure, billing practices, and comprehensive patient care. It would be reasonable to consider CCCs comparable to the oncology care model and incentivize the framework to achieve superior outcomes and long-term cost savings.

Lay Summary: Health care expenditures in young adults (aged 22-39 years) with acute lymphoblastic leukemia (ALL) are higher among patients at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) than those at non-CCCs. The CCC/non-CCC differences are significant among outpatient expenditures, which are driven by higher rates of outpatient hospital visits and outpatient hospital expenditures per visit at CCCs. Higher expenditures and visit rates of outpatient hospital visits among CCCs may also reflect how facility structure and billing patterns influence spending or comprehensive care. Young adults at CCCs face higher inpatient HPP expenditures; these are driven by serious adverse events.
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http://dx.doi.org/10.1002/cncr.33413DOI Listing
January 2021

The Future of Childhood Cancer Survivorship: Challenges and Opportunities for Continued Progress.

Pediatr Clin North Am 2020 12;67(6):1237-1251

Department of Epidemiology and Cancer Control, St. Jude. Children's Research Hospital, MS 735, 262 Danny Thomas Place, Memphis, TN 38105, USA.

As treatment evolves and the population who survive childhood cancer ages and increases in number, researchers must use novel approaches to prevent, identify and mitigate adverse effects of treatment. Future priorities include collaborative efforts to pool large cohort data to improve detection of late effects, identify late effects of novel therapies, and determine the contribution of genetic factors along with physiologic and accelerated aging among survivors. This knowledge should translate to individual risk prediction and prevention strategies. Finally, we must utilize health services research and implementation science to improve adoption of survivorship care recommendations outside of specialized pediatric oncology centers.
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http://dx.doi.org/10.1016/j.pcl.2020.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773506PMC
December 2020

Cardiovascular and Pulmonary Challenges After Treatment of Childhood Cancer.

Pediatr Clin North Am 2020 12;67(6):1155-1170

Childhood Cancer Research Platform, Institute of Social and Preventive Medicine, University of Bern, Mittelstrasse 43, Bern 3012, Switzerland; Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Mittelstrasse 43, Bern 3012, Switzerland.

Childhood cancer survivors are at risk for developing cardiovascular disease and pulmonary disease related to cancer treatment. This might not become apparent until many years after treatment and varies from subclinical to life-threatening disease. Important causes are anthracyclines and radiotherapy involving heart, head, or neck for cardiovascular disease, and bleomycin, busulfan, nitrosoureas, radiation to the chest, and lung or chest surgery for pulmonary disease. Most effects are dose dependent, but genetic risk factors have been discovered. Treatment options are limited. Prevention and regular screening are crucial. Survivors should be encouraged to adopt a healthy lifestyle, and modifiable risk factors should be addressed.
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http://dx.doi.org/10.1016/j.pcl.2020.07.007DOI Listing
December 2020

Subsequent Primary Neoplasms: Risks, Risk Factors, Surveillance, and Future Research.

Pediatr Clin North Am 2020 12;67(6):1135-1154

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, USA.

The authors' objective is to provide a brief update on recent advances in knowledge relating to subsequent primary neoplasms developing in survivors of childhood cancer. This includes a summary of established large-scale cohorts, risks reported, and contrasts with results from recently established large-scale cohorts of survivors of adolescent and young adult cancer. Recent evidence is summarized concerning the role of radiotherapy and chemotherapy for childhood cancer and survivor genomics in determining the risk of subsequent primary neoplasms. Progress with surveillance, screening, and clinical follow-up guidelines is addressed. Finally, priorities for future research are outlined.
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http://dx.doi.org/10.1016/j.pcl.2020.07.006DOI Listing
December 2020

Questionnaires assessing the use of complementary health approaches in pediatrics and their measurement properties: A systematic review.

Complement Ther Med 2020 Sep 26;53:102520. Epub 2020 Jul 26.

University of Toronto, Lawrence S. Bloomberg Faculty of Nursing, 155 College Street, Suite 130, Toronto, ON M5T 1P8, Canada; The Hospital for Sick Children, Child Health Evaluation Sciences, 555 University Avenue, Toronto, ON M5G 1X8, Canada.

Objectives: To identify questionnaires assessing the use of complementary health approaches (CHA) in pediatrics, describe their content, and appraise the methodological quality of the studies and the measurement properties of the questionnaires.

Method: Major electronic databases were searched from 2011 to 2020. Studies which aimed to assess the use of CHA and studies which reported developing and validating CHA questionnaires in pediatrics were included. Two reviewers independently screened the studies, extracted the data, and rated the methodological quality of the studies and measurement properties of the questionnaires using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. When consensus was not reached, a third reviewer was consulted.

Results: Thirty-eight studies were included. From these studies, 35 CHA questionnaires with a variety of different items were identified. Only two studies aimed to evaluate the measurement properties of two questionnaires. One questionnaire, available as a self- and proxy-report, was initially validated in children with juvenile idiopathic arthritis, and the other, available as an interviewer-administered questionnaire, was validated in children with cancer. According to the COSMIN, the methodological quality of both studies was inadequate or doubtful, and both questionnaires was not thoroughly validated.

Conclusion: This systematic review showed a lack of a thoroughly validated CHA questionnaire in pediatrics. However, two questionnaires were found to hold promise. To address this gap, one of the existing questionnaires should be adapted and further validated.
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http://dx.doi.org/10.1016/j.ctim.2020.102520DOI Listing
September 2020

Normative Values of High-Sensitivity Cardiac Troponin T and N-Terminal pro-B-Type Natriuretic Peptide in Children and Adolescents: A Study from the CALIPER Cohort.

J Appl Lab Med 2020 Sep 30. Epub 2020 Sep 30.

Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.

Background: Cardiac troponin (cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are increasingly used clinically to evaluate and prognosticate acute myocardial infarction and heart failure, respectively. Pediatric reference intervals and cut-offs have not been established for Roche's Elecsys Troponin T hs (high sensitive) assay. Although pediatric reference intervals exist for NT-proBNP, cut-off values do not exist. In this study, we report reference intervals and 99th percentile cut-offs in a large, healthy Canadian pediatric population using the CALIPER cohort.

Methods: Blood samples from 484 healthy children and adolescents between 0 and <19 years old were recruited from hospital outpatient clinics and community settings. Serum samples were analyzed using Roche's Cobas e411 and evaluated for high-sensitivity cTnT (hs-cTnT) and NT-proBNP concentrations. 95% reference intervals and 99th percentile cut-off values were established.

Results: Three hs-cTnT age partitions were established (0 to <6 months, 6 months to <1 year, and 1 to <19 years) with highest concentrations observed in children under 1 year. Two NT-proBNP age partitions were established (0 to <1 year, and 1 to <19 years), also with higher concentrations in infants under 1 year of age. For each of these age partitions, the 99th percentile cut-off, 95% reference interval, and proportion of detectable concentrations were determined.

Conclusions: This is the first study to examine hs-cTnT and NT-proBNP reference values together in a healthy pediatric cohort without other clinical indications. We present 99th percentile cut-offs, which will allow clinicians to appropriately evaluate cardiovascular disease in children and adolescents.
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http://dx.doi.org/10.1093/jalm/jfaa090DOI Listing
September 2020

Guidance regarding COVID-19 for survivors of childhood, adolescent, and young adult cancer: A statement from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Pediatr Blood Cancer 2020 12 23;67(12):e28702. Epub 2020 Sep 23.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Childhood, adolescent, and young adult (CAYA) cancer survivors may be at risk for a severe course of COVID-19. Little is known about the clinical course of COVID-19 in CAYA cancer survivors, or if additional preventive measures are warranted. We established a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) to summarize existing evidence and worldwide recommendations regarding evidence about factors/conditions associated with risk for a severe course of COVID-19 in CAYA cancer survivors, and to develop a consensus statement to provide guidance for healthcare practitioners and CAYA cancer survivors regarding COVID-19.
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http://dx.doi.org/10.1002/pbc.28702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537044PMC
December 2020

Cost-Effectiveness of the International Late Effects of Childhood Cancer Guideline Harmonization Group Screening Guidelines to Prevent Heart Failure in Survivors of Childhood Cancer.

J Clin Oncol 2020 Nov 14;38(33):3851-3862. Epub 2020 Aug 14.

Division of General Pediatrics, Boston Children's Hospital, Boston, MA.

Purpose: Survivors of childhood cancer treated with anthracyclines and/or chest-directed radiation are at increased risk for heart failure (HF). The International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) recommends risk-based screening echocardiograms, but evidence supporting its frequency and cost-effectiveness is limited.

Patients And Methods: Using the Childhood Cancer Survivor Study and St Jude Lifetime Cohort, we developed a microsimulation model of the clinical course of HF. We estimated long-term health outcomes and economic impact of screening according to IGHG-defined risk groups (low [doxorubicin-equivalent anthracycline dose of 1-99 mg/m and/or radiotherapy < 15 Gy], moderate [100 to < 250 mg/m or 15 to < 35 Gy], or high [≥ 250 mg/m or ≥ 35 Gy or both ≥ 100 mg/m and ≥ 15 Gy]). We compared 1-, 2-, 5-, and 10-year interval-based screening with no screening. Screening performance and treatment effectiveness were estimated based on published studies. Costs and quality-of-life weights were based on national averages and published reports. Outcomes included lifetime HF risk, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). Strategies with ICERs < $100,000 per QALY gained were considered cost-effective.

Results: Among the IGHG risk groups, cumulative lifetime risks of HF without screening were 36.7% (high risk), 24.7% (moderate risk), and 16.9% (low risk). Routine screening reduced this risk by 4% to 11%, depending on frequency. Screening every 2, 5, and 10 years was cost-effective for high-risk survivors, and every 5 and 10 years for moderate-risk survivors. In contrast, ICERs were > $175,000 per QALY gained for all strategies for low-risk survivors, representing approximately 40% of those for whom screening is currently recommended.

Conclusion: Our findings suggest that refinement of recommended screening strategies for IGHG high- and low-risk survivors is needed, including careful reconsideration of discontinuing asymptomatic left ventricular dysfunction and HF screening in low-risk survivors.
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http://dx.doi.org/10.1200/JCO.20.00418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676889PMC
November 2020

Longitudinal Changes in Echocardiographic Parameters of Cardiac Function in Pediatric Cancer Survivors.

JACC CardioOncol 2020 Mar 17;2(1):26-37. Epub 2020 Mar 17.

Clinical Research and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Childhood cancer survivors undergo serial echocardiograms to screen for cardiotoxicity. It is not clear whether small longitudinal changes in functional or structural parameters over time have clinical significance.

Objectives: To assess the timing of changes in serial echocardiographic parameters in pediatric age childhood cancer survivors and to evaluate their associations with cardiomyopathy development.

Methods: We performed a multi-center retrospective case-control study of ≥1-year survivors following the end of cancer therapy. Cardiomyopathy cases (fractional shortening (FS) ≤28% or ejection fraction (EF) ≤50% on ≥2 occasions) were matched to controls (FS ≥30%, EF ≥55%, not on cardiac medications) by cumulative anthracycline and chest radiation dose, follow-up duration, and age at diagnosis. Digitally archived clinical surveillance echocardiograms were quantified in a central core lab, blinded to patient characteristics. Using mixed models with interaction terms between time and case status, we estimated the least square mean differences of 2D, M-mode, pulsed wave Doppler and tissue Doppler imaging derived parameters across time between cases and controls.

Results: We identified 50 matched case-control pairs from 5 centers. Analysis of 412 echocardiograms (cases, n=181; controls, n=231) determined that indices of LV systolic function (FS, biplane EF), diastolic function (mitral E/A ratio), and LV size (end diastolic dimension z-scores) were significantly different between cases and controls, even four years prior to the development of cardiomyopathy.

Conclusions: Longitudinal changes in cardiac functional parameters can occur relatively early in pediatric age childhood cancer survivors and are associated with the development of cardiomyopathy.
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http://dx.doi.org/10.1016/j.jaccao.2020.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384713PMC
March 2020

Reduced Morbidity and Mortality in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study.

J Clin Oncol 2020 10 24;38(29):3418-3429. Epub 2020 Jul 24.

Division of Hematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Purpose: Risk-stratified therapy, which modifies treatment on the basis of clinical and biologic features, has improved 5-year overall survival of childhood acute lymphoblastic leukemia (ALL) to 90%, but its impact on long-term toxicity remains unknown.

Methods: We assessed all-cause and health-related late mortality (including late effects of cancer therapy), subsequent malignant neoplasms (SMNs), chronic health conditions, and neurocognitive outcomes among 6,148 survivors of childhood ALL (median age, 27.9 years; range, 5.9-61.9 years) diagnosed between 1970 and 1999. Therapy combinations and treatment intensity defined 6 groups: 1970s-like (70s), standard- or high-risk 1980s-like (80sSR, 80sHR) and 1990s-like (90sSR, 90sHR), and relapse/transplantation (R/BMT). Cumulative incidence, standardized mortality ratios, and standardized incidence ratios were compared between treatment groups and with the US population.

Results: Overall, 20-year all-cause late mortality was 6.6% (95% CI, 6.0 to 7.1). Compared with 70s, 90sSR and 90sHR experienced lower health-related late mortality (rate ratio [95% CI]: 90sSR, 0.2 [0.1 to 0.4]; 90sHR, 0.3 [0.1 to 0.7]), comparable to the US population (standardized mortality ratio [95% CI]: 90sSR, 1.3 [0.8 to 2.0]; 90sHR, 1.7 [0.7 to 3.5]). Compared with 70s, 90sSR had a lower rate of SMN (rate ratio [95% CI], 0.3 [0.1 to 0.6]) that was not different from that of the US population (standardized incidence ratio [95% CI], 1.0 [0.6 to 1.6]). The 90sSR group had fewer severe chronic health conditions than the 70s (20-year cumulative incidence [95% CI], 11.0% [9.7% to 12.3%] 22.5% [19.4% to 25.5%]) and a lower prevalence of impaired memory (prevalence ratio [95% CI], 0.7 [0.6 to 0.9]) and task efficiency (0.5 [0.4 to 0.7]).

Conclusion: Risk-stratified therapy has reduced late morbidity and mortality among contemporary survivors of standard-risk ALL, represented by 90sSR. Health-related late mortality and SMN risks among 5-year survivors of contemporary, standard-risk childhood ALL are comparable to the general population.
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http://dx.doi.org/10.1200/JCO.20.00493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527155PMC
October 2020

Severe infections following treatment for childhood cancer: a report from CYP-C.

Leuk Lymphoma 2020 12 12;61(12):2876-2884. Epub 2020 Jul 12.

Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.

Little is known about infections occurring after childhood cancer treatment. We assessed the risk of severe infection postcancer therapy in survivors of leukemia compared to other cancer types. We performed a population-based cohort study of children <15 years of age diagnosed with cancer (2001-2016), alive and relapse-free 30 days after treatment completion. The risk of severe infection in both groups was estimated using subdistribution proportional hazard regression. We identified 6148 survivors (1960 with leukemia). The cumulative incidence (95% confidence interval) of severe infections at 3 years was 0.70% (0.40-1.2%) in leukemia and 0.51% (0.32-0.79%) in other cancers. The risk of severe infection was not statistically different in leukemia survivors compared to other cancer types in univariate and multivariate analysis (adjusted hazard ratio: 1.40, 95% CI: 0.69-2.85). No significant association was found between a history of leukemia and an increased risk of severe infection after treatment, compared to other cancer types.
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http://dx.doi.org/10.1080/10428194.2020.1789626DOI Listing
December 2020

Effect of anthracycline therapy on myocardial function and markers of fibrotic remodelling in childhood cancer survivors.

Eur Heart J Cardiovasc Imaging 2020 Jun 14. Epub 2020 Jun 14.

Department of Paediatrics, The Hospital for Sick Children, University of Toronto, 555 University Ave., Toronto, M5G 1X8, ON, Canada.

Aims: Anthracyclines are a cornerstone of paediatric cancer treatment. We aimed to quantify myocardial cardiac magnetic resonance (CMR) native T1 (NT1) and extracellular volume fraction (ECV) as markers of fibrosis in a cohort of childhood cancer survivors (CCS).

Methods And Results: A cohort of CCS in remission underwent CMR T1 mapping. Diastolic function was assessed by echocardiography. Results were compared to a cohort of normal controls of similar age and gender. Fifty-five CCS and 46 controls were included. Both groups had similar mean left ventricular (LV) NT1 values (999 ± 36 vs. 1007 ± 32 ms, P = 0.27); ECV was higher (25.6 ± 6.9 vs. 20.7 ± 2.4%, P = 0.003) and intracellular mass was lower (37.5 ± 8.4 vs. 43.3 ± 9.9g/m2, P = 0.02) in CCS. The CCS group had lower LV ejection fraction (EF) and LV mass index with otherwise normal diastolic function in all but one patient. The proportion of subjects with elevated ECV compared to controls did not differ between subgroups with normal or reduced LV EF (22% vs. 28%; P = 0.13) and no correlations were found between LVEF and ECV. While average values remained within normal range, mitral E/E' (6.6 ± 1.6 vs. 5.9 ± 0.9, P = 0.02) was higher in CCS. Neither NT1 nor ECV correlated with diastolic function indices or cumulative anthracycline dose.

Conclusions: There is evidence for mild diffuse extracellular volume expansion in some asymptomatic CCS; myocyte loss could be part of the mechanism, accompanied by subtle changes in systolic and diastolic function. These findings suggest mild myocardial damage and remodelling after anthracycline treatment in some CCS which requires continued monitoring.
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http://dx.doi.org/10.1093/ehjci/jeaa093DOI Listing
June 2020

Long-Term Incidence and Predictors of Significant Hearing Loss Requiring Hearing Assistive Devices Among Childhood Cancer Survivors: A Population-Based Study.

J Clin Oncol 2020 08 28;38(23):2639-2646. Epub 2020 May 28.

ICES, Toronto, Ontario, Canada.

Purpose: Hearing loss is a significant late effect among childhood cancer survivors. Recent guidelines note insufficient evidence to quantify its natural history or risk associated with specific exposures. We examined the long-term incidence and predictors of hearing loss requiring hearing amplification devices (HADs) using population-based health care data.

Methods: In Ontario, Canada, HAD costs are subsidized by the Assistive Devices Program (ADP). Ontario children < 18 years of age at cancer diagnosis between 1987 and 2016 were identified and linked to ADP claims. Cumulative HAD incidence was compared between cases and matched controls. Patient, disease, and treatment predictors of HAD were examined.

Results: We identified 11,842 cases and 59,210 controls. Cases were at higher risk for HAD (hazard ratio [HR], 12.8; 95% CI, 9.8 to 16.7; < .001). The cumulative incidence of HAD among survivors was 2.1% (95% CI, 1.7% to 2.5%) at 20 years and 6.4% (95% CI, 2.8% to 12.1%) at 30 years post-diagnosis. The 30-year incidence was highest in neuroblastoma (10.7%; 95% CI, 3.8% to 21.7%) and hepatoblastoma (16.2%; 95% CI, 8.6% to 26.0%) survivors. Predictors of HAD in multivariable analyses included age 0-4 years at diagnosis ( 5-9 years; HR, 2.2; 95% CI, 1.4-3.3; < .001). Relative to no cisplatin exposure, patients receiving < 200 mg/m were not at greater risk, unlike those receiving higher cumulative doses. Relative to no cranial or facial radiation, those who had received ≤ 32.00 Gy were at no higher risk, unlike those who had received > 32.00 Gy. Carboplatin exposure was not associated with HAD.

Conclusion: Childhood cancer survivors are at elevated risk for requiring HAD, which continues to increase between 20 and 30 years after diagnosis. Thresholds of cisplatin and radiation exposure exist, above which risk substantially increases. Prolonged monitoring and trials of otoprotective agents are warranted in high-risk populations.
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http://dx.doi.org/10.1200/JCO.19.03166DOI Listing
August 2020

Treatment patterns and outcomes in adolescents and young adults with Hodgkin lymphoma in pediatric versus adult centers: An IMPACT Cohort Study.

Cancer Med 2020 Oct 22;9(19):6933-6945. Epub 2020 May 22.

Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.

Hodgkin lymphoma (HL) is a common adolescent and young adult (AYA) cancer. While outcome disparities between pediatric vs. adult centers [locus of care (LOC)] have been demonstrated in other AYA cancers such as acute lymphoblastic leukemia, they have not been well studied in HL. We therefore compared population-based treatment patterns and outcomes in AYA HL by LOC. The IMPACT Cohort includes data on all Ontario, Canada AYA (15-21 years) diagnosed with HL between 1992 and 2012. Linkage to population-based health administrative data identified late effects. We examined LOC-based differences in treatment modalities, cumulative doses, event-free survival (EFS), overall survival (OS), and late effects. Among 954 AYA, 711 (74.5%) received therapy at adult centers. Pediatric center AYA experienced higher rates of radiation therapy but lower cumulative doses of doxorubicin and bleomycin. 10-year EFS did not differ between pediatric vs. adult cancer vs. community centers (83.8% ± 2.4% vs. 82.8% ± 1.6% vs. 82.7%±3.0%; P = .71); LOC was not significantly associated with either EFS or OS in multivariable analyses. Higher incidences of second malignancies in pediatric center AYA and of cardiovascular events in adult center AYA were observed, but were not significant. In conclusion, while pediatric and adult centers used different treatment strategies, outcomes were equivalent. Differences in treatment exposures are however likely to result in different late-effect risks. Protocol choice should be guided by individual late-effect risk.
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http://dx.doi.org/10.1002/cam4.3138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541154PMC
October 2020

Consistent Physical Activity and Future Neurocognitive Problems in Adult Survivors of Childhood Cancers: A Report From the Childhood Cancer Survivor Study.

J Clin Oncol 2020 06 24;38(18):2041-2052. Epub 2020 Apr 24.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Purpose: To investigate longitudinal associations between physical activity (PA) and neurocognitive problems in adult survivors of childhood cancer.

Methods: A total of 12,123 5-year survivors diagnosed between 1970 and 1999 (median [range] age at diagnosis, 7 [0-21] years, time since diagnosis at baseline, 16 [6-30] years) and 720 siblings self-reported PA and neurocognitive problems. PA was collected at baseline, and PA and neurocognitive data were obtained 7 (1-12) years and 12 (9-14) years later. PA consistency was defined as any combination of ≥ 75 minutes of vigorous or 150 minutes of moderate activity per week on all surveys. Multiple linear regressions, conducted separately for CNS and non-CNS survivors, identified associations between PA consistency and neurocognitive outcomes (expected mean, 50; standard deviation [SD], 10). Mediating effects of body mass index (BMI) and chronic health conditions (CHCs) were evaluated.

Results: Survivors were less likely than siblings to report consistent PA (28.1% 33.6%) and more likely to report problems in Task Efficiency (T-scores mean ± SD: siblings, 50.0 ± 0.4; CNS, 61.4 ± 0.4; non-CNS, 53.3 ± 0.3), Emotion Regulation (siblings, 51.4 ± 0.4; CNS, 54.5 ± 0.3; non-CNS 53.4 ± 0.2), and Memory (siblings, 50.8 ± 0.4; CNS, 58.9 ± 0.4; non-CNS, 53.5 ± 0.2; all < .001). Survivors of CNS cancers (52.8 ± 0.3) also reported poorer Organization than siblings (49.9 ± 0.4; < .001). After adjusting for age at diagnosis, age at questionnaire, emotional distress, and cancer treatment exposures, consistent PA was associated with fewer neurocognitive problems compared with consistent inactivity for both CNS and non-CNS groups (T-score differences ranging from -7.9 to -2.2) and larger neurocognitive improvements over time (-6.0 to -2.5), all ≤ .01. BMI and severe CHCs partially mediated the PA-neurocognitive associations, but the mediation effects were small (change in β ≤ 0.4).

Conclusion: Adult survivors of childhood cancer who report more consistent PA have fewer neurocognitive problems and larger improvements in these concerns many years after treatment.
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http://dx.doi.org/10.1200/JCO.19.02677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302957PMC
June 2020

Current and coming challenges in the management of the survivorship population.

Semin Oncol 2020 02 4;47(1):23-39. Epub 2020 Mar 4.

Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

With the widespread adoption of multimodality treatment, 5-year survival of children diagnosed with cancer has improved dramatically in the past several decades from approximately 60% in 1970 to greater than 85% currently. As a result, there are an estimated nearly half a million long-term survivors of childhood cancer living in the United States today. However, survivors have, on average, significantly greater serious medical and psychosocial late effects compared with the general population. In this review, we will discuss the current epidemiology of childhood cancer survivorship, including new methods to estimate the burden of late effects and genetic susceptibility toward late effects. We will also review the development of surveillance guidelines for childhood cancer survivors and early toxicity signals from novel agents now being tested and used increasingly to treat pediatric and adult cancers. We conclude with an overview of current models of survivorship care and areas for future research.
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http://dx.doi.org/10.1053/j.seminoncol.2020.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227387PMC
February 2020

Pain Squad+ smartphone app to support real-time pain treatment for adolescents with cancer: protocol for a randomised controlled trial.

BMJ Open 2020 03 16;10(3):e037251. Epub 2020 Mar 16.

Child Health Evaluative Sciences, Hospital for Sick Children, Toronto, Ontario, Canada.

Introduction: Pain negatively affects the health-related quality of life (HRQL) of adolescents with cancer. The Pain Squad+ smartphone-based application (app), has been developed to provide adolescents with real-time pain self-management support. The app uses a validated pain assessment and personalised pain treatment advice with centralised decision support via a registered nurse to enable real-time pain treatment in all settings. The algorithm informing pain treatment advice is evidence-based and expert-vetted. This trial will longitudinally evaluate the impact of Pain Squad+, with or without the addition of nurse support, on adolescent health and cost outcomes.

Methods And Analysis: This will be a pragmatic, multicentre, waitlist controlled, 3-arm parallel-group superiority randomised trial with 1:1:1 allocation enrolling 74 adolescents with cancer per arm from nine cancer centres. Participants will be 12 to 18 years, English-speaking and with ≥3/10 pain. Exclusion criteria are significant comorbidities, end-of-life status or enrolment in a concurrent pain study. The primary aim is to determine the effect of Pain Squad+, with and without nurse support, on pain intensity in adolescents with cancer, when compared with a waitlist control group. The secondary aims are to determine the immediate and sustained effect over time of using Pain Squad+, with and without nurse support, as per prospective outcome measurements of pain interference, HRQL, pain self-efficacy and cost. Linear mixed models with baseline scores as a covariate will be used. Qualitative interviews with adolescents from all trial arms will be conducted and analysed.

Ethics And Dissemination: This trial is approved by the Hospital for Sick Children Research Ethics Board. Results will provide data to guide adolescents with cancer and healthcare teams in treating pain. Dissemination will occur through partnerships with stakeholder groups, scientific meetings, publications, mass media releases and consumer detailing.

Trial Registration Number: NCT03632343 ().
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http://dx.doi.org/10.1136/bmjopen-2020-037251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076249PMC
March 2020

Comparing Childhood Cancer Care Costs in Two Canadian Provinces.

Healthc Policy 2020 02;15(3):76-88

Senior Scientist and Director, THETA Collaborative, Toronto General Hospital Research Institute, University Health Network, Toronto, ON.

Background: Cancer in children presents unique issues for diagnosis, treatment and survivorship care. Phase-specific comparative cost estimates are important for informing healthcare planning.

Objective: The aim of this paper is to compare direct medical costs of childhood cancer by phase of care in British Columbia (BC) and Ontario (ON).

Methods: For cancer patients diagnosed at <15 years of age and propensity-score-matched non-cancer controls, we applied standard costing methodology using population-based healthcare administrative data to estimate and compare phase-based costs by province.

Results: Phase-specific cancer-attributable costs were 2%-39% higher for ON than for BC. Leukemia pre-diagnosis costs and annual lymphoma continuing care costs were >50% higher in ON. Phase-specific in-patient hospital costs (the major cost category) represented 63%-82% of ON costs, versus 43%-73% of BC costs. Phase-specific diagnostic tests and procedures accounted for 1.0%-3.4% of ON costs and 2.8%-13.0% of BC costs.

Conclusion: There are substantial cost differences between these two Canadian provinces, BC and ON, possibly identifying opportunities for healthcare planning improvement.
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http://dx.doi.org/10.12927/hcpol.2020.26129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075448PMC
February 2020

Adherence to Surveillance for Second Malignant Neoplasms and Cardiac Dysfunction in Childhood Cancer Survivors: A Childhood Cancer Survivor Study.

J Clin Oncol 2020 05 6;38(15):1711-1722. Epub 2020 Mar 6.

The Hospital for Sick Children, Toronto, Ontario, Canada.

Purpose: To evaluate childhood cancer survivors' adherence to surveillance protocols for late effects of treatment and to determine the factors affecting adherence.

Methods: Between 2014 and 2016, 11,337 survivors and 2,146 siblings in the Childhood Cancer Survivor Study completed a survey ascertaining adherence to Children's Oncology Group (COG) guidelines for survivors at high risk for second malignant neoplasms or cardiac dysfunction and to the American Cancer Society (ACS) cancer screening guidelines for average-risk populations. Adherence rates and factors affecting adherence were analyzed.

Results: Median age at diagnosis was 7 years (range, 0-20.9 years), and median time from diagnosis was 29 years (range, 15-47 years). Among high-risk survivors, adherence to COG breast, colorectal, skin, and cardiac surveillance was 12.6% (95% CI, 10.0% to 15.3%), 37.0% (34.1% to 39.9%), 22.3% (21.2% to 23.4%), and 41.4% (40.1% to 42.7%), respectively. Among average-risk survivors, adherence to ACS breast, cervical, and colorectal screening was 57.1% (53.2% to 61.0%), 83.6% (82.7% to 84.5%), and 68.5% (64.7% to 72.2%), respectively. Twenty-seven percent of survivors and 20.0% of primary care providers (PCPs) had a survivorship care plan (SCP). For high-risk survivors, SCP possession was associated with increased adherence to COG breast (22.3% . 8.1%; prevalence ratio [PR], 2.52; CI, 1.59 to 4.01), skin (34.8% 23.0%; PR, 1.16; CI, 1.01 to 1.33), and cardiac (67.0% 33.1%; PR, 1.73; CI, 1.55 to 1.92) surveillance. For high-risk survivors, PCP possession of a SCP was associated only with increased adherence to COG skin cancer surveillance (36.9% 23.2%; PR, 1.24; CI, 1.08 to 1.43).

Conclusion: Guideline adherence is suboptimal. Although survivor SCP possession is associated with better adherence, few survivors and PCPs have one. New strategies to improve adherence are needed.
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http://dx.doi.org/10.1200/JCO.19.01825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357338PMC
May 2020

Late mortality and chronic health conditions in long-term survivors of early-adolescent and young adult cancers: a retrospective cohort analysis from the Childhood Cancer Survivor Study.

Lancet Oncol 2020 03 14;21(3):421-435. Epub 2020 Feb 14.

Department of Pediatrics, University of Chicago, Chicago, IL, USA. Electronic address:

Background: Treatment outcomes among survivors of cancer diagnosed during adolescence and early young adulthood have not been characterised independently of survivors of cancers diagnosed during childhood. We aimed to describe chronic health conditions and all-cause and cause-specific mortality among survivors of early-adolescent and young adult cancer.

Methods: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort study with longitudinal follow-up of 5-year survivors diagnosed with cancer before the age of 21 years at 27 academic institutions in the USA and Canada between 1970 and 1999. We evaluated outcomes among survivors of early-adolescent and young adult cancer (aged 15-20 years at diagnosis) and survivors diagnosed at age younger than 15 years (matched on primary cancer diagnosis, including leukaemia, lymphoma, CNS tumours, neuroblastoma, Wilms tumour, soft-tissue sarcomas, and bone cancer) by comparing both groups to siblings of the same age. Mortality was ascertained with the National Death Index. Chronic health conditions were classified with the Common Terminology Criteria for Adverse Events. Standardised mortality ratios (SMRs) were estimated with age-specific, sex-specific, and calendar year-specific US rates. Cox proportional hazard models estimated hazard ratios (HRs) for chronic health conditions and 95% CIs.

Findings: Among 5804 early-adolescent and young adult survivors (median age 42 years, IQR 34-50) the SMR compared to the general population for all-cause mortality was 5·9 (95% CI 5·5-6·2) and among 5804 childhood cancer survivors (median age 34 years; 27-42), it was 6·2 (5·8-6·6). Early-adolescent and young adult survivors had lower SMRs for death from health-related causes (ie, conditions that exclude recurrence or progression of the primary cancer and external causes, but include the late effects of cancer therapy) than did childhood cancer survivors (SMR 4·8 [95% CI 4·4-5·1] vs 6·8 [6·2-7·4]), which was primarily evident more than 20 years after cancer diagnosis. Early-adolescent and young adult cancer survivors and childhood cancer survivors were both at greater risk of developing severe and disabling, life-threatening, or fatal (grade 3-5) health conditions than siblings of the same age (HR 4·2 [95% CI 3·7-4·8] for early adolescent and young adult cancer survivors and 5·6 [4·9-6·3] for childhood cancer survivors), and at increased risk of developing grade 3-5 cardiac (4·3 [3·5-5·4] and 5·6 [4·5-7·1]), endocrine (3·9 [2·9-5·1] and 6·4 [5·1-8·0]), and musculoskeletal conditions (6·5 [3·9-11·1] and 8·0 [4·6-14·0]) when compared with siblings of the same age, although all these risks were lower for early-adolescent and young adult survivors than for childhood cancer survivors.

Interpretation: Early-adolescent and young adult cancer survivors had higher risks of mortality and severe and life threatening chronic health conditions than the general population. However, early-adolescent and young adult cancer survivors had lower non-recurrent, health-related SMRs and relative risks of developing grade 3-5 chronic health conditions than childhood cancer survivors, by comparison with siblings of the same age, which were most notable more than 20 years after their original cancer. These results highlight the need for long-term screening of both childhood and early-adolescent and young adult cancer survivors.

Funding: National Cancer Institute and American Lebanese-Syrian Associated Charities.
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http://dx.doi.org/10.1016/S1470-2045(19)30800-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392388PMC
March 2020

Predicting acute ovarian failure in female survivors of childhood cancer: a cohort study in the Childhood Cancer Survivor Study (CCSS) and the St Jude Lifetime Cohort (SJLIFE).

Lancet Oncol 2020 03 14;21(3):436-445. Epub 2020 Feb 14.

School of Public Health, University of Alberta, Edmonton, AB, Canada. Electronic address:

Background: Cancer treatment can cause gonadal impairment. Acute ovarian failure is defined as the permanent loss of ovarian function within 5 years of cancer diagnosis. We aimed to develop and validate risk prediction tools to provide accurate clinical guidance for paediatric patients with cancer.

Methods: In this cohort study, prediction models of acute ovarian failure risk were developed using eligible female US and Canadian participants in the Childhood Cancer Survivor Study (CCSS) cohort and validated in the St Jude Lifetime Cohort (SJLIFE) Study. 5-year survivors from the CCSS cohort were included if they were at least 18 years old at their most recent follow-up and had complete treatment exposure and adequate menstrual history (including age at menarche, current menstrual status, age at last menstruation, and menopausal aetiology) information available. Participants in the SJLIFE cohort were at least 10-year survivors. Participants were excluded from the prediction analysis if they had an ovarian hormone deficiency, had missing exposure information, or had indeterminate ovarian status. The outcome of acute ovarian failure was defined as permanent loss of ovarian function within 5 years of cancer diagnosis or no menarche after cancer treatment by the age of 18 years. Logistic regression, random forest, and support vector machines were used as candidate methods to develop the risk prediction models in the CCSS cohort. Prediction performance was evaluated internally (in the CCSS cohort) and externally (in the SJLIFE cohort) using the areas under the receiver operating characteristic curve (AUC) and the precision-recall curve (average precision [AP; average positive predictive value]).

Findings: Data from the CCSS cohort were collected for participants followed up between Nov 3, 1992, and Nov 25, 2016, and from the SJLIFE cohort for participants followed up between Oct 17, 2007, and April 16, 2012. Of 11 336 female CCSS participants, 5886 (51·9%) met all inclusion criteria for analysis. 1644 participants were identified from the SJLIFE cohort, of whom 875 (53·2%) were eligible for analysis. 353 (6·0%) of analysed CCSS participants and 50 (5·7%) of analysed SJLIFE participants had acute ovarian failure. The overall median follow-up for the CCSS cohort was 23·9 years (IQR 20·4-27·9), and for SJLIFE it was 23·9 years (19·0-30·0). The three candidate methods (logistic regression, random forest, and support vector machines) yielded similar results, and a prescribed dose model with abdominal and pelvic radiation doses and an ovarian dose model with ovarian radiation dosimetry using logistic regression were selected. Common predictors in both models were history of haematopoietic stem-cell transplantation, cumulative alkylating drug dose, and an interaction between age at cancer diagnosis and haematopoietic stem-cell transplant. External validation of the model in the SJLIFE cohort produced an estimated AUC of 0·94 (95% CI 0·90-0·98) and AP of 0·68 (95% CI 0·53-0·81) for the ovarian dose model, and AUC of 0·96 (0·94-0·97) and AP of 0·46 (0·34-0·61) for the prescribed dose model. Based on these models, an online risk calculator has been developed for clinical use.

Interpretation: Both acute ovarian failure risk prediction models performed well. The ovarian dose model is preferred if ovarian radiation dosimetry is available. The models, along with the online risk calculator, could help clinical discussions regarding the need for fertility preservation interventions in girls and young women newly diagnosed with cancer.

Funding: Canadian Institutes of Health Research, Women and Children's Health Research Institute, National Cancer Institute, and American Lebanese Syrian Associated Charities.
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http://dx.doi.org/10.1016/S1470-2045(19)30818-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060129PMC
March 2020

Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada.

JAMA Oncol 2020 03;6(3):393-401

Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.

Importance: Tisagenlecleucel, a chimeric antigen receptor T-cell therapy for relapsed or refractory pediatric acute lymphoblastic leukemia, has been approved for use in multiple jurisdictions. The public list price is US $475 000, or more than CaD $600 000. Assessing the cost-effectiveness of tisagenlecleucel is necessary to inform policy makers on the economic value of this treatment.

Objective: To assess the value for money of tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible pediatric patients with acute lymphoblastic leukemia under unknown long-term effectiveness.

Design, Setting, And Participants: A cost-utility analysis of tisagenlecleucel compared with current standard care using a Canadian population-based registry of pediatric patients with acute lymphoblastic leukemia was performed. Results from 3 pooled single-arm tisagenlecleucel clinical trials and a provincial pediatric cancer registry were combined to create treatment and control arms, respectively. The population-based control arm consisted of patients meeting clinical trial inclusion and exclusion criteria, starting at second relapse. Multistate and individual-level simulation modeling were combined to predict patient lifetime health trajectories by treatment strategy. Tisagenlecleucel efficacy was modeled across long-term cure rates, from 10% to 40%, to account for limited information on its long-term effectiveness. Uncertainty was tested with 1-way and probabilistic sensitivity analysis. Data were collected in September 2017, and analysis began in December 2017.

Exposures: Tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible patients.

Main Outcomes And Measures: Relative health care costs, survival gains, and quality-adjusted life-years (QALYs) between tisagenlecleucel and current standard care.

Results: The treatment and control arms were modeled on 192 and 118 patients, respectively. The mean (SD) age of control individuals was 10 (4.25) years, and the mean (SD) age of the pooled clinical trial sample was 11 (6) years. The control individuals had 78 boys (66%), and the pooled clinical trial sample had 102 boys (53%). Treatment with tisagenlecleucel was associated with an additional 2.14 to 9.85 life years or 1.68 to 6.61 QALYs, compared with current care. The average additional cost of tisagenlecleucel was CaD $470 013 (US $357 031). Accounting for the total discounted cost over the patient lifetime resulted in an incremental cost of CaD $71 000 (US $53 933) to CaD $281 000 (US $213 453) per QALY gain.

Conclusions And Relevance: To our knowledge, this study offers the first cost-effectiveness analysis of tisagenlecleucel compared with current standard care for pediatric patients with acute lymphoblastic leukemia using a constructed population-based control arm. At a willingness-to-pay threshold of $150 000/QALY, tisagenlecleucel had a 32% likelihood of being cost-effective. Tisagenlecleucel cost-effectiveness would fall below $50 000/QALY with a long-term cure rate of over 0.40 or a price discount of 49% at its currently known effectiveness.
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http://dx.doi.org/10.1001/jamaoncol.2019.5909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990832PMC
March 2020

Infections as a potential long-term risk following childhood leukemia.

Med Hypotheses 2020 Apr 7;137:109554. Epub 2020 Jan 7.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, 555, University Avenue, Toronto, Ontario M5G 1X8, Canada; Program in Child Health Evaluative Sciences, The Hospital for Sick Children, 686, Bay St., Toronto, Ontario, Canada.

Leukemia is the most common childhood cancer. While infections are a frequent and potentially severe complication while on treatment, less is known about the risk for infections following therapy completion. In this article, we propose that leukemia survivors might be at increased risk of infections following therapy completion than the general population, independently of potential confounders such as age, sex and Down syndrome. This association is conceivably due to several factors. First, therapy-induced immune dysfunction of both the humoral and cellular compartments appears to last for several years following anti-cancer therapy and after hematopoietic stem cell transplantation. Second, clinical and epidemiological research has shown leukemia survivors are disproportionally affected by comorbidities related to leukemia treatment and its complications, such as diabetes and obesity, which may induce secondary immunodeficiency and infections. Last, differences in health-related behaviors between leukemia survivors and the general population (such as re-vaccination practices) may affect the baseline risk of infections. Although under-represented in the epidemiological literature as a possible late effect of childhood leukemia and its treatment, it is plausible that leukemia survivors are at increased risk of infections for several years when compared to the general population and their siblings. Further research is needed to empirically test these hypotheses.
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http://dx.doi.org/10.1016/j.mehy.2020.109554DOI Listing
April 2020

Communicating health information and improving coordination with primary care (CHIIP): Rationale and design of a randomized cardiovascular health promotion trial for adult survivors of childhood cancer.

Contemp Clin Trials 2020 02 17;89:105915. Epub 2019 Dec 17.

Department of Medicine, Duke University, Durham, NC, United States of America.

Background: Long-term survival for children diagnosed with cancer exceeds 80%. Notably, premature cardiovascular disease has become the leading non-cancer cause of late mortality among these survivors.

Methods/design: This randomized controlled trial (RCT; NCT03104543) focuses on adult participants in the Childhood Cancer Survivor Study identified as high risk for ischemic heart disease or heart failure due to their cancer treatment. Participants undergo a home-based evaluation of blood pressure and laboratory tests to determine the prevalence of undiagnosed and/or undertreated hypertension, dyslipidemia, and diabetes. Those with abnormal values are then enrolled in an RCT to test the efficacy of a 12-month personalized, remotely delivered survivorship care plan (SCP) intervention designed to reduce undertreatment of these three target conditions. The intervention approximates a clinical encounter and is based on chronic disease self-management strategies.

Results: With a goal of 750, currently 342 out of 742 eligible participants approached have enrolled (46.1%). Initially, we randomized participants to different recruitment strategies, including shorter approach packets and a tiered consent, but did not find significant differences in participation rates (40.7% to 42.9%; p = .95). Subsequently, slightly greater participation was seen with larger upfront unconditional incentive checks ($50 vs. $25: 50.7% vs. 44.1%; p = .10). Overall, the financial impact of the $50 upfront incentive was cost neutral, and possibly cost-saving, vs. a $25 upfront incentive.

Conclusion: The overall study will determine if a National Academy of Medicine-recommended SCP intervention can improve cardiovascular outcomes among long-term survivors of childhood cancer. Modifications to the recruitment strategy may improve participation rates over time.
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http://dx.doi.org/10.1016/j.cct.2019.105915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242131PMC
February 2020

Echocardiographic Assessment of Cardiac Function in Pediatric Survivors of Anthracycline-Treated Childhood Cancer.

Circ Cardiovasc Imaging 2019 12 12;12(12):e008869. Epub 2019 Dec 12.

Division of Cardiology (M.G.S., C.F., C.S., W.H., M.K.F., C.-P.S.F., C.M., S.M., L.M.), The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Anthracycline-induced cardiotoxicity is a major cause of morbidity and mortality in childhood cancer survivors (CCSs). Echocardiographic myocardial strain imaging is recommended in adult patients with cancer, but its role in pediatric CCSs has not been well established. Aims of this study were to determine the prevalence of abnormalities in left ventricular strain in pediatric CCSs, to compare strain with other echocardiographic measurements and blood biomarkers, and to explore risk factors for reduced strain.

Methods: CCSs ≥3 years from their last anthracycline treatment were enrolled in this multicenter study and underwent a standardized functional echocardiogram and biomarker collection. Regression analysis was used to identify factors associated with longitudinal strain (LS).

Results: Five hundred forty-six pediatric CCSs were compared with 134 healthy controls. Abnormal left ventricular ejection fraction (<50%) and mean LS ( score, <-2) was found in 0.8% and 7.7% of the CCSs, respectively. LS was significantly lower in CCSs than in controls, but the absolute difference was small (0.7%). Lower LS in CCSs was associated with older current age and higher body surface area. Sex, cumulative anthracycline dose, radiotherapy, and biomarkers were not independently associated with LS. Circumferential strain, diastolic parameters, and biomarkers were not significantly different in pediatric CCSs.

Conclusions: Global systolic function and LS are only mildly reduced in pediatric CCSs, and most LS values are within normal range. This makes single LS measurements of limited added value in identifying CCSs at risk for cardiac dysfunction. The utility of strain imaging in the long-term follow-up of CCS remains to be demonstrated.
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http://dx.doi.org/10.1161/CIRCIMAGING.119.008869DOI Listing
December 2019

Prevalence and Predictors of Frailty in Childhood Cancer Survivors and Siblings: A Report From the Childhood Cancer Survivor Study.

J Clin Oncol 2020 01 4;38(3):232-247. Epub 2019 Dec 4.

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

Purpose: To estimate the prevalence of frailty among childhood cancer survivors and to determine the direct and indirect effects of treatment exposures, lifestyle factors, and severe, disabling, and life-threatening chronic condition on frailty.

Methods: Childhood cancer survivors (≥ 5 years since diagnosis), treated between 1970 and 1999 when < 21 years old (n = 10,899; mean age, 37.6 ± 9.4 years; 48% male, 86% white) and siblings were included (n = 2,097; mean age, 42.9 ± 9.4 years). Frailty was defined as ≥ 3 of the following: low lean mass, exhaustion, low energy expenditure, walking limitations, and weakness. Generalized linear models were used to evaluate direct and indirect associations between frailty and treatment exposures, sociodemographic characteristics, lifestyle factors, and chronic condition.

Results: The overall prevalence of frailty among survivors was 3 times higher compared with siblings (6.4%; 95% CI, 4.1% to 8.7%; 2.2%; 95% CI, 1.2% to 3.2%). Survivors of CNS tumors (9.5%; 95% CI, 5.2% to 13.8%) and bone tumors (8.1%; 95% CI, 5.1% to 11.1%) had the highest prevalence of frailty. Survivors exposed to cranial radiation, pelvic radiation ≥ 34 Gy, abdominal radiation > 40 Gy, cisplatin ≥ 600 mg/m, amputation, or lung surgery had increased risk for frailty. These associations were partially but not completely attenuated when sociodemographic characteristics, lifestyle factors, and chronic conditions were added to multivariable models. Cranial radiation (prevalence ratio [PR], 1.47; 95% CI, 1.20 to 1.76), pelvic radiation ≥ 34 Gy (PR, 1.46; 95% CI, 1.01 to 2.11), and lung surgery (PR, 1.75; 95% CI, 1.28 to 2.38) remained significant after sociodemographic, lifestyle, and chronic conditions were accounted for.

Conclusion: Childhood cancer survivors reported a higher prevalence of frailty compared with siblings. Radiation and lung surgery exposures were associated with increased risk for frailty. Interventions to prevent, delay onset, or remediate chronic disease and/or promote healthy lifestyle are needed to decrease the prevalence of frailty and preserve function in this at-risk population.
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http://dx.doi.org/10.1200/JCO.19.01226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968796PMC
January 2020