Publications by authors named "Rebecca M Howell"

114 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

Evaluation of a multiview architecture for automatic vertebral labeling of palliative radiotherapy simulation CT images.

Med Phys 2020 Nov 15;47(11):5592-5608. Epub 2020 Sep 15.

Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Purpose: The purpose of this work was to evaluate the performance of X-Net, a multiview deep learning architecture, to automatically label vertebral levels (S2-C1) in palliative radiotherapy simulation CT scans.

Methods: For each patient CT scan, our automated approach 1) segmented spinal canal using a convolutional-neural network (CNN), 2) formed sagittal and coronal intensity projection pairs, 3) labeled vertebral levels with X-Net, and 4) detected irregular intervertebral spacing using an analytic methodology. The spinal canal CNN was trained via fivefold cross validation using 1,966 simulation CT scans and evaluated on 330 CT scans. After labeling vertebral levels (S2-C1) in 897 palliative radiotherapy simulation CT scans, a volume of interest surrounding the spinal canal in each patient's CT scan was converted into sagittal and coronal intensity projection image pairs. Then, intensity projection image pairs were augmented and used to train X-Net to automatically label vertebral levels using fivefold cross validation (n = 803). Prior to testing upon the final test set (n = 94), CT scans of patients with anatomical abnormalities, surgical implants, or other atypical features from the final test set were placed in an outlier group (n = 20), whereas those without these features were placed in a normative group (n = 74). The performance of X-Net, X-Net Ensemble, and another leading vertebral labeling architecture (Btrfly Net) was evaluated on both groups using identification rate, localization error, and other metrics. The performance of our approach was also evaluated on the MICCAI 2014 test dataset (n = 60). Finally, a method to detect irregular intervertebral spacing was created based on the rate of change in spacing between predicted vertebral body locations and was also evaluated using the final test set. Receiver operating characteristic analysis was used to investigate the performance of the method to detect irregular intervertebral spacing.

Results: The spinal canal architecture yielded centroid coordinates spanning S2-C1 with submillimeter accuracy (mean ± standard deviation, 0.399 ± 0.299 mm; n = 330 patients) and was robust in the localization of spinal canal centroid to surgical implants and widespread metastases. Cross-validation testing of X-Net for vertebral labeling revealed that the deep learning model performance (F score, precision, and sensitivity) improved with CT scan length. The X-Net, X-Net Ensemble, and Btrfly Net mean identification rates and localization errors were 92.4% and 2.3 mm, 94.2% and 2.2 mm, and 90.5% and 3.4 mm, respectively, in the final test set and 96.7% and 2.2 mm, 96.9% and 2.0 mm, and 94.8% and 3.3 mm, respectively, within the normative group of the final test set. The X-Net Ensemble yielded the highest percentage of patients (94%) having all vertebral bodies identified correctly in the final test set when the three most inferior and superior vertebral bodies were excluded from the CT scan. The method used to detect labeling failures had 67% sensitivity and 95% specificity when combined with the X-Net Ensemble and flagged five of six patients with atypical vertebral counts (additional thoracic (T13), additional lumbar (L6) or only four lumbar vertebrae). Mean identification rate on the MICCAI 2014 dataset using an X-Net Ensemble was increased from 86.8% to 91.3% through the use of transfer learning and obtained state-of-the-art results for various regions of the spine.

Conclusions: We trained X-Net, our unique convolutional neural network, to automatically label vertebral levels from S2 to C1 on palliative radiotherapy CT images and found that an ensemble of X-Net models had high vertebral body identification rate (94.2%) and small localization errors (2.2 ± 1.8 mm). In addition, our transfer learning approach achieved state-of-the-art results on a well-known benchmark dataset with high identification rate (91.3%) and low localization error (3.3 mm ± 2.7 mm). When we pre-screened radiotherapy CT images for the presence of hardware, surgical implants, or other anatomic abnormalities prior to the use of X-Net, it labeled the spine correctly in more than 97% of patients and 94% of patients when scans were not prescreened. Automatically generated labels are robust to widespread vertebral metastases and surgical implants and our method to detect labeling failures based on neighborhood intervertebral spacing can reliably identify patients with an additional lumbar or thoracic vertebral body.
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http://dx.doi.org/10.1002/mp.14415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756475PMC
November 2020

Genome-wide Association Studies Reveal Novel Locus With Sex-/Therapy-Specific Fracture Risk Effects in Childhood Cancer Survivors.

J Bone Miner Res 2020 Dec 18. Epub 2020 Dec 18.

School of Public Health, University of Alberta, Edmonton, Canada.

Childhood cancer survivors treated with radiation therapy (RT) and osteotoxic chemotherapies are at increased risk for fractures. However, understanding of how genetic and clinical susceptibility factors jointly contribute to fracture risk among survivors is limited. To address this gap, we conducted genome-wide association studies of fracture risk after cancer diagnosis in 2453 participants of European ancestry from the Childhood Cancer Survivor Study (CCSS) with 930 incident fractures using Cox regression models (ie, time-to-event analysis) and prioritized sex- and treatment-stratified genetic associations. We performed replication analyses in 1417 survivors of European ancestry with 652 incident fractures from the St. Jude Lifetime Cohort Study (SJLIFE). In discovery, we identified a genome-wide significant (p < 5 × 10 ) fracture risk locus, 16p13.3 (HAGHL), among female CCSS survivors (n = 1289) with strong evidence of sex-specific effects (p  < 7 × 10 ). Combining discovery and replication data, rs1406815 showed the strongest association (hazard ratio [HR] = 1.43, p = 8.2 × 10 ; n = 1935 women) at this locus. In treatment-stratified analyses in the discovery cohort, the association between rs1406815 and fracture risk among female survivors with no RT exposures was weak (HR = 1.22, 95% confidence interval [CI] 0.95-1.57, p = 0.11) but increased substantially among those with greater head/neck RT doses (any RT: HR = 1.88, 95% CI 1.54-2.28, p = 2.4 × 10 ; >36 Gray only: HR = 3.79, 95% CI 1.95-7.34, p = 8.2 × 10 ). These head/neck RT-specific HAGHL single-nucleotide polymorphism (SNP) effects were replicated in female SJLIFE survivors. In silico bioinformatics analyses suggest these fracture risk alleles regulate HAGHL gene expression and related bone resorption pathways. Genetic risk profiles integrating this locus may help identify female survivors who would benefit from targeted interventions to reduce fracture risk. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4234DOI Listing
December 2020

The Contribution of Stress and Distress to Cardiovascular Health in Adult Survivors of Childhood Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Feb 24;30(2):286-294. Epub 2020 Nov 24.

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

Background: Childhood cancer survivors are at risk for cardiovascular morbidity and mortality that is not fully explained by cancer-directed therapies. We examined the contribution of emotional stress and distress to cardiac health in adult survivors of childhood cancer.

Methods: Participants included 3,267 adult survivors enrolled in the St. Jude Lifetime Cohort Study [median (range) 29.9 (18.1-64.5) years of age; 7.7 (0-24.8) years at diagnosis; 48.4% female]. Survivors completed comprehensive medical assessments and standardized measures of depression, anxiety, posttraumatic stress symptoms (PTSS), and perceived stress. Cardiovascular-related conditions included hypertension, diabetes, dyslipidemia, cardiomyopathy, dysrhythmia, myocardial infarction (severity graded 0-4), and metabolic syndrome (yes/no). Multivariable modified Poisson models examined associations between symptoms of stress/distress and cardiovascular outcomes. Longitudinal associations between stress/distress and new-onset cardiovascular outcomes, defined as a change from grade ≤1 at initial evaluation to grade ≥2 at follow-up (median 3.9 years) were examined in 1,748 participants.

Results: In multivariable cross-sectional models, stress/distress was associated with hypertension [risk ratio (RR) = 1.24; 95% confidence interval (CI), 1.07-1.43], dyslipidemia (RR = 1.29; 95% CI, 1.03-1.61), and metabolic syndrome (RR = 1.35; 95% CI, 1.17-1.54) independent of known cardiovascular risk factors. In longitudinal models, stress/distress was associated with new-onset dysrhythmia (RR = 2.87; 95% CI, 1.21-6.78), perceived stress with hypertension (RR = 1.42; 95% CI, 1.04-1.95), and PTSS and anxiety with dyslipidemia (RR = 1.72; 95% CI, 1.13-2.62; RR = 1.54; 95% CI, 1.01-2.35, respectively).

Conclusions: Stress/distress is independently associated with adverse cardiovascular outcomes among childhood cancer survivors.

Impact: Improving psychological health may serve as a potential intervention target for optimizing cardiac health among childhood cancer survivors.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872134PMC
February 2021

Prescription Psychoactive Medication Use in Adolescent Survivors of Childhood Cancer and Association With Adult Functional Outcomes.

JNCI Cancer Spectr 2020 Oct 29;4(5):pkaa057. Epub 2020 Jun 29.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.

Background: This study estimates the prevalence and identifies predictors of psychoactive medication use in adolescent survivors of childhood cancer (aged 12-18 years) and its associations with functional outcomes at young adulthood (aged 18-28 years).

Methods: This retrospective cohort study includes 5665 adolescent survivors of childhood cancer at no less than 5 years postdiagnosis (53.8% male, median age = 15 years, interquartile range [IQR] = 13-16 years) and 921 adolescent sibling controls. Parent-reported psychoactive medication use during adolescence was collected at baseline. After a median of 8 years, functional outcomes and social attainment were self-reported during adulthood (n = 3114, median age = 22 years, IQR = 20-24 years). Multivariable log-binomial models evaluated associations among risk factors, medication use, and adult outcomes.

Results: Higher prevalence of psychoactive medication use was reported in survivors compared with siblings (18.3% vs 6.6%; 2-sided < .001), with trends for increasing antidepressant and stimulant use in recent treatment eras. After adjusting for cancer treatment and baseline cognitive problems, psychoactive medication use during adolescence was associated with impaired task efficiency (relative risk [RR] = 1.20, 95% confidence interval [CI] = 1.01 to 1.43) and memory (RR = 1.27, 95% CI = 1.05 to 1.52) during adulthood. Survivors who reported continued use of medications from adolescence to adulthood demonstrated poorer emotional regulation (RR = 1.68, 95% CI = 1.24 to 2.27) and organization (RR = 1.82, 95% CI = 1.28 to 2.59) compared with nonusers. Adolescent opioid use was associated with somatization symptoms (RR = 1.72, 95% CI = 1.09 to 2.73) during adulthood, after adjusting for cancer treatment and baseline behavioral problems. They were also more likely to not complete college (RR = 1.21, 95% CI = 1.04 to 1.41) or work full-time (RR = 1.60, 95% CI = 1.23 to 2.08) compared with nonusers.

Conclusion: Use of psychoactive medication is more prevalent among adolescent survivors compared with siblings and does not normalize adult outcomes, as evidenced by poorer functional outcomes during young adulthood.
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http://dx.doi.org/10.1093/jncics/pkaa057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583158PMC
October 2020

Psychological, educational, and social late effects in adolescent survivors of Wilms tumor: A report from the Childhood Cancer Survivor Study.

Psychooncology 2020 Oct 28. Epub 2020 Oct 28.

Neuropsychology Division, Children's National Health System, Washington, District of Columbia, USA.

Objective: To delineate the impact of treatment exposures and chronic health conditions on psychological, educational, and social outcomes in adolescent survivors of Wilms tumor.

Methods: Parent reports from the Childhood Cancer Survivor Study were analyzed for 666 adolescent survivors of Wilms tumor and 698 adolescent siblings. Adjusting for race and household income, survivors were compared to siblings on the Behavior Problems Index and educational outcomes. Multivariable modified Poisson regression estimated relative risks (RR) for therapeutic exposures and chronic health conditions (CTCAE 4.03 graded) among survivors, adjusting for sex, race, income, and age at diagnosis.

Results: Compared to siblings, adolescent survivors of Wilms tumor were more likely to take psychoactive medication (9.4% vs. 5.1%, p < 0.001) and utilize special education services (25.5% vs. 12.6%, p < 0.001) but did not differ significantly in emotional and behavioral problems. Survivors were less likely to be friendless (7.2% vs. 10.1%, p = 0.04) but were more likely to have difficulty getting along with friends (14.5% vs. 7.8%, p < 0.001). Among survivors, use of special education services was associated with abdomen plus chest radiation (RR = 1.98, CI:1.18-3.34). Those with grade 2-4 cardiovascular conditions had higher risk for anxiety/depression (RR = 1.95, CI:1.19-3.19), headstrong behaviors (RR = 1.91, CI:1.26-2.89), and inattention (RR = 1.56, CI:1.02-2.40).

Conclusions: Adolescent survivors of Wilms tumor were similar to siblings with respect to mental health concerns overall but were more likely to require special education. Monitoring of psychosocial and academic problems through adolescence is warranted, especially among those treated with radiation to the abdomen plus chest or with cardiac conditions.
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http://dx.doi.org/10.1002/pon.5584DOI Listing
October 2020

Cardiac biomarkers and association with subsequent cardiomyopathy and mortality among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort.

Cancer 2021 Feb 27;127(3):458-466. Epub 2020 Oct 27.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Survivors of childhood cancer exposed to cardiotoxic therapies are at significant cardiovascular risk. The utility of cardiac biomarkers for identifying the risk of future cardiomyopathy and mortality is unknown.

Methods: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) were assessed in 1213 adults 10 or more years from a childhood cancer diagnosis; 786 were exposed to anthracycline chemotherapy and/or chest-directed radiation therapy (RT). NT-proBNP values above age- and sex-specific 97.5th percentiles were considered abnormal. Generalized linear models estimated cross-sectional associations between abnormal NT-proBNP and anthracycline or chest RT doses as risk ratios with 95% confidence intervals (CIs). A Poisson distribution estimated rates and a Cox proportional hazards model estimated hazard ratios (HRs) for future cardiac events and death.

Results: At a median age of 35.5 years (interquartile range, 29.8-42.5 years), NT-proBNP and cTnT were abnormal in 22.5% and 0.4%, respectively. Exposure to chest RT and exposure to anthracycline chemotherapy were each associated with a dose-dependent increased risk for abnormal NT-proBNP (P for trend <.0001). Among exposed survivors with no history of Common Terminology Criteria for Adverse Events-graded cardiomyopathy and with normal systolic function, survivors with abnormal NT-proBNP had higher rates per 1000 person-years of cardiac mortality (2.93 vs 0.96; P < .0001) and future cardiomyopathy (32.10 vs 15.98; P < .0001) and an increased risk of future cardiomyopathy (HR, 2.28; 95% CI, 1.28-4.08) according to a multivariable assessment.

Conclusions: Abnormal NT-proBNP values were prevalent and, among survivors who were exposed to cardiotoxic therapy but did not have a history of cardiomyopathy or current systolic dysfunction, identified those at increased risk for future cardiomyopathy. Further longitudinal studies are needed to confirm this novel finding.
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http://dx.doi.org/10.1002/cncr.33292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855049PMC
February 2021

Development and validation of an age-scalable cardiac model with substructures for dosimetry in late-effects studies of childhood cancer survivors.

Radiother Oncol 2020 Dec 17;153:163-171. Epub 2020 Oct 17.

Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, United States; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, United States. Electronic address:

Background And Purpose: Radiation therapy is a risk factor for late cardiac disease in childhood cancer survivors. Several pediatric cohort studies have established whole heart dose and dose-volume response models. Emerging data suggest that dose to cardiac substructures may be more predictive than whole heart metrics. In order to develop substructure dose-response models, the heart model previously used for pediatric cohort dosimetry needed enhancement and substructure delineation.

Methods: To enhance our heart model, we combined the age-scalable capability of our computational phantom with the anatomically-delineated (with substructures) heart models from an international humanoid phantom series. We examined cardiac volume similarity/overlap between registered age-scaled phantoms (1, 5, 10, and 15 years) with the enhanced heart model and the reference phantoms of the same age; dice similarity coefficient (DSC) and overlap coefficient (OC) were calculated for each matched pair. To assess the accuracy of our enhanced heart model, we compared doses from computed tomography-based planning (ground truth) with reconstructed heart doses. We also compared doses calculated with the prior and enhanced heart models for a cohort of nearly 5000 childhood cancer survivors.

Results: We developed a realistic cardiac model with 14-substructures, scalable across a broad age range (1-15 years); average DSC and OC were 0.84 ± 0.05 and 0.90 ± 0.05, respectively. The average percent difference between reconstructed and ground truth mean heart doses was 4.2%. In the cohort dosimetry analysis, dose and dose-volume metrics were approximately 10% lower on average when the enhanced heart model was used for dose reconstructions.

Conclusion: We successfully developed and validated an anatomically realistic age-scalable cardiac model that can be used to establish substructure dose-response models for late cardiac disease in childhood cancer survivor cohorts.
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http://dx.doi.org/10.1016/j.radonc.2020.10.017DOI Listing
December 2020

Cardiovascular Family History Increases Risk for Late-Onset Adverse Cardiovascular Outcomes in Childhood Cancer Survivors: A St. Jude Lifetime Cohort Report.

Cancer Epidemiol Biomarkers Prev 2021 Jan 8;30(1):123-132. Epub 2020 Oct 8.

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

Background: Survivors of childhood cancer have an increased risk of therapy-related cardiovascular disease. It is not known whether family history of cardiovascular disease further increases risk of adverse cardiovascular outcomes among survivors.

Methods: Family history of cardiovascular disease was collected from 1,260 survivors [median age at diagnosis, 8 years (range, 0-23); age at last follow-up, 35 years (range, 18-66)] of childhood cancer in the St. Jude Lifetime Cohort Study. Multivariable risk models evaluated associations with cardiovascular disease (Common Terminology Criteria for Adverse Events grade 2-4 events) and cardiovascular risk factors.

Results: Among survivors exposed to chest-directed radiation and/or anthracycline chemotherapy ( = 824), 7% reported a first-degree family history of heart failure, 19% myocardial infarction, 11% stroke, 26% atherosclerotic disease (myocardial infarction and/or stroke), 62% hypertension, and 31% diabetes mellitus. Eighteen percent of exposed survivors developed heart failure, 9% myocardial infarction, 3% stroke, 11% atherosclerotic disease, 30% hypertension, and 9% diabetes mellitus. Having a first-degree family history of atherosclerotic disease was independently associated with development of treatment-related heart failure [RR, 1.38; 95% confidence interval (CI), 1.01-1.88; = 0.04] among exposed survivors. Risk for hypertension was increased among exposed survivors with a first-degree family history of hypertension (RR, 1.55; 95% CI, 1.26-1.92; < 0.0001) or of any cardiovascular disease [myocardial infarction, stroke, or heart failure (RR, 1.30; 95% CI, 1.06-1.59; = 0.01)].

Conclusions: Family history of cardiovascular disease and cardiovascular risk factors independently increased risk of heart failure and hypertension among survivors of childhood cancer exposed to cardiotoxic therapies.

Impact: These data show the importance of cardiovascular family history as a risk factor for cardiovascular disease in survivors of childhood cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855495PMC
January 2021

Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study.

JCO Precis Oncol 2020 21;4. Epub 2020 Aug 21.

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

Purpose: Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown.

Patients And Methods: We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based values using a Bonferroni-corrected significance threshold of < 8.06 × 10.

Results: Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; = 4.79 × 10), most notably but nonsignificantly for (patient cases, 4.0%; matched controls, 0.6%; = 9.64 × 10). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with variants (patient cases, 1.8%; controls, 0.4%; = 3.31 × 10), another gene implicated in DNA double-strand break repair.

Conclusion: In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.
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http://dx.doi.org/10.1200/PO.20.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469586PMC
August 2020

Dose-response relationships for radiation-related heart disease: Impact of uncertainties in cardiac dose reconstruction.

Radiother Oncol 2020 Dec 3;153:155-162. Epub 2020 Sep 3.

Nuffield Department of Population Health, University of Oxford, Oxford, UK; Oxford Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Background And Purpose: Radiation-related heart disease (RRHD) can occur many decades after thoracic radiotherapy for Hodgkin lymphoma (HL) or childhood cancer (CC). To quantify the likely risk of RRHD for patients treated today, dose-response relationships derived from patients treated in previous decades are used. Publications presenting these dose-response relationships usually include estimates of uncertainties in the risks but ignore the effect of uncertainties in the reconstructed cardiac doses.

Materials/methods: We assessed the systematic and random uncertainties in the reconstructed doses for published dose-response relationships for RRHD risk in survivors of HL or CC. Using the same reconstruction methods as were used in the original publications, we reconstructed mean heart doses and, wherever possible, mean left-ventricular doses for an independent case-series of test patients. These patients had known, CT-based, cardiac doses which were compared with the reconstructed doses to estimate the magnitude of the uncertainties and their effect on the dose-response relationships.

Results: For all five reconstruction methods the relationship between reconstructed and CT-based doses was linear. For all but the simplest reconstruction method, the dose uncertainties were moderate, the effect of the systematic uncertainty on the dose-response relationships was less than 10%, and the effects of random uncertainty were small except at the highest doses.

Conclusions: These results increase confidence in the published dose-response relationships for the risk of RRHD in HL and CC survivors. This may encourage doctors to use these dose-response relationships when estimating individualised risks for patients-an important aspect of personalising radiotherapy treatments today.
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http://dx.doi.org/10.1016/j.radonc.2020.08.022DOI Listing
December 2020

Body Composition, Metabolic Health, and Functional Impairment among Adults Treated for Abdominal and Pelvic Tumors during Childhood.

Cancer Epidemiol Biomarkers Prev 2020 Sep 13;29(9):1750-1758. Epub 2020 Aug 13.

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

Background: We aimed to characterize body composition, metabolic impairments, and physical performance among survivors of pediatric abdominal and pelvic solid tumors.

Methods: Participants included 431 survivors of abdominal or pelvic tumors [median attained age = 29.9 (range: 18.7-55.1) years]. Relative lean mass and fat mass were assessed with dual X-ray absorptiometry. Metabolic outcomes [insulin resistance (IR), high-density lipoprotein (HDL), low-density lipoprotein, and triglycerides] were based on laboratory values and medication usage. General linear regression evaluated associations between treatment and lifestyle with body composition; binomial regression evaluated associations between body composition and metabolic outcomes and physical performance.

Results: Lean mass was lower than values from the National Health and Nutrition Examination Survey (NHANES) in males (Z-score = -0.67 ± 1.27; < 0.001) and females (Z-score = -0.72 ± 1.28; < 0.001). Higher cumulative abdominal and pelvic radiation doses were associated with lower lean mass among males [abdominal: β = -0.22 (SE) ± 0.07; = 0.002 and pelvic: β = -0.23 ± 0.07; = 0.002] and females (abdominal: β = -0.30 ± 0.09; = 0.001 and pelvic: β = -0.16 ± 0.08; = 0.037). Prevalence of IR (40.6% vs. 33.8%; = 0.006), low HDL (28.9% vs. 33.5%; = 0.046), and high triglycerides (18.4% vs. 10.0%; < 0.001) was increased among survivors relative to NHANES. Compared with survivors with normal/high lean mass and normal/low fat mass, survivors with normal/high lean mass and high fat mass had an increased risk of IR ( < 0.001), low HDL ( < 0.001), reduced quadriceps strength at 60°/second ( < 0.001) and 300°/second ( < 0.001), and reduced distance covered in the 6-minute walk ( < 0.01).

Conclusions: Abdominal/pelvic radiotherapy is associated with body composition changes that can adversely influence metabolic outcomes and performance status among survivors.

Impact: Interventions targeting body composition may facilitate management of cardiovascular disease risk in this population.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721344PMC
September 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

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

Dose-volume effects of breast cancer radiation therapy on the risk of second oesophageal cancer.

Radiother Oncol 2020 Oct 15;151:33-39. Epub 2020 Jul 15.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, United States.

Purpose: To investigate the relationship between oesophagus dose-volume distribution and long-term risk of oesophageal cancer after radiation therapy for breast cancer.

Materials And Methods: In a case-control study nested within a cohort of 289,748 ≥5-year survivors of female breast cancer treated in 1943-2003 in five countries, doses to the second primary cancer (D) and individual dose-volume histograms (DVH) to the entire oesophagus were reconstructed for 252 oesophageal cancer cases and 488 matched controls (median follow-up time: 13, range: 5-37 years). Using conditional logistic regression, we estimated excess odds ratios (EOR) of oesophageal cancer associated with DVH metrics. We also investigated whether DVH metrics confounded or modified D-related -risk estimates.

Results: Among the DVH metrics evaluated, median dose (D) to the entire oesophagus had the best statistical performance for estimating risk of all histological types combined (EOR/Gy = 0.071, 95% confidence interval [CI]: 0.018 to 0.206). For squamous cell carcinoma, the most common subtype, the EOR/Gy for D increased by 31% (95% CI: 3% to 205%) for each increment of 10% of V30 (p = 0.02). Adjusting for DVH metrics did not materially change the EOR/Gy for D, but there was a borderline significant positive interaction between D and V30 (p = 0.07).

Conclusion: This first study investigating the relationship between oesophagus dose-volume distribution and oesophageal cancer risk showed an increased risk per Gy for D with larger volumes irradiated at high doses. While current techniques allows better oesophagus sparing, constraints applied to D and V30 could potentially further reduce the risk of oesophageal cancer.
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http://dx.doi.org/10.1016/j.radonc.2020.07.022DOI Listing
October 2020

Sensitivity of IROC phantom performance to radiotherapy treatment planning system beam modeling parameters based on community-driven data.

Med Phys 2020 Oct 16;47(10):5250-5259. Epub 2020 Aug 16.

Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Purpose: Treatment planning system (TPS) dose calculations have previously been shown to be sensitive to modeling errors, especially when treating with complex strategies like intensity-modulated radiation therapy (IMRT). This work investigates the dosimetric impact of several dosimetric and nondosimetric beam modeling parameters, based on their distribution in the radiotherapy community, in two commercial TPSs in order to understand the realistic potential for dose deviations and their clinical effects.

Methods And Materials: Beam models representing standard 120-leaf Varian Clinac-type machines were developed in Eclipse 13.5 (AAA algorithm) and RayStation 9A (v8.99, collapsed-cone algorithm) based upon median values of dosimetric measurements from Imaging and Radiation Oncology Core (IROC) Houston site visit data and community beam modeling parameter survey data in order to represent a baseline linear accelerator. Five clinically acceptable treatment plans (three IMRT, two VMAT) were developed for the IROC head and neck phantom. Dose distributions for each plan were recalculated after individually modifying parameters of interest (e.g., MLC transmission, percent depth doses [PDDs], and output factors) according to the 2.5th to 97.5 percentiles of community survey and machine performance data to encompass the realistic extent of variance in the radiotherapy community. The resultant dose distributions were evaluated by examining relative changes in average dose for thermoluminescent dosimeter (TLD) locations across the two target volumes and organ at risk (OAR). Interplay was also examined for parameters generating changes in target dose greater than 1%.

Results: For Eclipse, dose calculations were sensitive to changes in the dosimetric leaf gap (DLG), which resulted in differences from -5% to +3% to the targets relative to the baseline beam model. Modifying the MLC transmission factor introduced differences up to ± 1%. For RayStation, parameters determining MLC behaviors likewise contributed substantially; the MLC offset introduced changes in dose from -4% to +7%, and the MLC transmission caused changes of -4% to +2%. Among the dosimetric qualities examined, changes in PDD implementation resulted in the most substantial changes, but these were only up to ±1%. Other dosimetric factors had <1% impact on dose accuracy. Interplay between impactful parameters was found to be minimal.

Conclusion: Factors related to the modeling of the MLC, particularly relating to the leaf offset, can cause clinically significant changes in the calculated dose for IMRT and VMAT plans. This should be of concern to the radiotherapy community because the clinical effects of poor TPS commissioning were based on reported data from clinically implemented beam models. These results further reinforce that dose errors caused by poor TPS calculations are often involved in IROC phantom failures.
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http://dx.doi.org/10.1002/mp.14396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689833PMC
October 2020

3D-printed headrest for frameless Gamma Knife radiosurgery: Design and validation.

J Appl Clin Med Phys 2020 Sep 30;21(9):6-15. Epub 2020 Jun 30.

Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Purpose: Frameless Gamma Knife stereotactic radiosurgery (SRS) uses a moldable headrest with a thermoplastic mask for patient immobilization. An efficacious headrest is time consuming and difficult to fabricate due to the expertise required to mold the headrest within machine geometrical limitations. The purpose of this study was to design and validate a three-dimensional (3D)-printed headrest for frameless Gamma Knife SRS that can overcome these difficulties.

Materials And Methods: A headrest 3D model designed to fit within the frameless adapter was 3D printed. Dosimetric properties of the 3D-printed headrest and a standard-of-care moldable headrest were compared by delivering a Gamma Knife treatment to an anthropomorphic head phantom fitted with an ionization chamber and radiochromic film. Ionization measurements were compared to assess headrest attenuation and a gamma index was calculated to compare the film dose distributions. A volunteer study was conducted to assess the immobilization efficacy of the 3D-printed headrest compared to the moldable headrest. Five volunteers had their head motion tracked by a surface tracking system while immobilized in each headrest for 20 min. The recorded motion data were used to calculate the average volunteer movement and a paired t-test was performed.

Results: The ionization chamber readings were within 0.55% for the 3D-printed and moldable headrests, and the calculated gamma index showed 98.6% of points within dose difference of 2% and 2 mm distance to agreement for the film measurement. These results demonstrate that the headrests were dosimetrically equivalent within the experimental uncertainties. Average motion (±standard deviation) of the volunteers while immobilized was 1.41 ± 0.43 mm and 1.36 ± 0.51 mm for the 3D-printed and moldable headrests, respectively. The average observed volunteer motion between headrests was not statistically different, based on a P-value of 0.466.

Conclusions: We designed and validated a 3D-printed headrest for immobilizing patients undergoing frameless Gamma Knife SRS.
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http://dx.doi.org/10.1002/acm2.12956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497935PMC
September 2020

Association of Exercise Intolerance With Emotional Distress, Attainment of Social Roles, and Health-Related Quality of Life Among Adult Survivors of Childhood Cancer.

JAMA Oncol 2020 08;6(8):1194-1202

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

Importance: Exercise intolerance is associated with increased risk for morbidity and mortality in childhood cancer survivors. However, an association between exercise intolerance and psychosocial outcomes has not been fully explored.

Objective: To examine the associations between exercise intolerance and emotional distress, attainment of social roles, and health-related quality of life in childhood cancer survivors.

Design, Setting, And Participants: A cross-sectional study including 1041 adult survivors of childhood cancer and 286 community controls in the St Jude Lifetime Cohort was conducted at St Jude Children's Research Hospital. The study was performed from April 1, 2012, to March 15, 2020.

Exposures: Exercise intolerance was defined as relative peak oxygen uptake less than 85% of age- and sex-estimated levels from maximal cardiopulmonary exercise testing.

Main Outcomes And Measures: Emotional distress was measured with the 18-item Brief Symptom Inventory-18, which includes overall Global Severity Index and depression, anxiety, and somatization subscales. Participants with T scores greater than or equal to 63 were classified as having elevated levels of distress. Social attainment was evaluated using patient-reported educational, employment, and marital status. Health-related quality of life was examined with the Medical Outcomes Survey Short Form-36. Participants with T scores less than or equal to 40 were classified as reporting poor health-related quality of life.

Results: Of the 1041 participants, 528 were women (50.7%). The prevalence of exercise intolerance among survivors (mean [SD] age, 35.5 [9.2] years) was higher than that among controls (age, 34.5 [10.0] years) (survivors: 634 [60.9%] vs controls: 75 [26.2%], P < .001). After adjusting for age at diagnosis and cardiopulmonary exercise testing, sex, race/ethnicity, smoking, physical activity, and exercise intolerance were associated with an increased risk for anxiety (prevalence rate ratio [PRR], 1.95; 95% CI, 1.20-3.16), somatization (PRR, 1.86; 95% CI, 1.23-2.80), and unemployment (PRR, 1.76; 95% CI, 1.23-2.52); an inverse association was noted with having a college degree (PRR, 0.67; 95% CI, 0.50-0.88). Exercise intolerance was associated with an increased the risk for scoring less than or equal to 40 on the physical component summary of the Medical Outcomes Survey Short Form-36 (PRR, 3.69; 95% CI, 2.34-5.84). These associations persisted when either cancer treatment exposures or chronic health conditions were added to the model.

Conclusions And Relevance: The findings of this study suggest that exercise intolerance is independently associated with emotional distress, attainment of social roles, and health-related quality of life of long-term survivors of childhood cancer. The results also suggest that improving physiologic capacity may benefit general health and wellness, as well as emotional health, ability to participate in social roles, and health-related quality of life.
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http://dx.doi.org/10.1001/jamaoncol.2020.2054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317652PMC
August 2020

Dose calculation errors as a component of failing IROC lung and spine phantom irradiations.

Med Phys 2020 Sep 23;47(9):4502-4508. Epub 2020 Jun 23.

The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.

Purpose: Between July 2013 and August 2019, 22% of the imaging and radiation oncology core (IROC) spine, and 15% of the moving lung phantom irradiations have failed to meet established acceptability criteria. The spine phantom simulates a highly modulated stereotactic body radiation therapy (SBRT) case, whereas the lung phantom represents a low-to-none modulation moving target case. In this study, we assessed the contribution of dose calculation errors to these phantom results and evaluated their effects on failure rates.

Methods: We evaluated dose calculation errors by comparing the calculation accuracy of various institutions' treatment planning systems (TPSs) vs IROC-Houston's previously established independent dose recalculation system (DRS). Each calculation was compared with the measured dose actually delivered to the phantom; cases in which the recalculation was more accurate were interpreted as a deficiency in the institution's TPS. A total of 258 phantom irradiation plans (172 lung and 86 spine) were recomputed.

Results: Overall, the DRS performed better than the TPSs in 47% of the spine phantom cases. However, the DRS was more accurate in 93% of failing spine phantom cases (with an average improvement of 2.35%), indicating a deficiency in the institution's treatment planning system. Deficiencies in dose calculation accounted for 60% of the overall discrepancy between measured and planned doses among spine phantoms. In contrast, lung phantom DRS calculations were more accurate in only 35% and 42% of all and failing lung phantom cases respectively, indicating that dose calculation errors were not substantially present. These errors accounted for only 30% of the overall discrepancy between measured and planned doses.

Conclusions: Dose calculation errors are common and substantial in IROC spine phantom irradiations, highlighting a major failure mode in this phantom and in clinical treatment management of these cases. In contrast, dose calculation accuracy had only a minimal contribution to failing lung phantom results, indicating that other failure modes drive problems with this phantom and similar clinical treatments.
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http://dx.doi.org/10.1002/mp.14258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686159PMC
September 2020

Automatic Verification of Beam Apertures for Cervical Cancer Radiation Therapy.

Pract Radiat Oncol 2020 Sep - Oct;10(5):e415-e424. Epub 2020 May 23.

Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Purpose: Automated tools can help identify radiation treatment plans of unacceptable quality. To this end, we developed a quality verification technique to automatically verify the clinical acceptability of beam apertures for 4-field box treatments of patients with cervical cancer. By comparing the beam apertures to be used for treatment with a secondary set of beam apertures developed automatically, this quality verification technique can flag beam apertures that may need to be edited to be acceptable for treatment.

Methods And Materials: The automated methodology for creating verification beam apertures uses a deep learning model trained on beam apertures and digitally reconstructed radiographs from 255 clinically acceptable planned treatments (as rated by physicians). These verification apertures were then compared with the treatment apertures using spatial comparison metrics to detect unacceptable treatment apertures. We tested the quality verification technique on beam apertures from 80 treatment plans. Each plan was rated by physicians, where 57 were rated clinically acceptable and 23 were rated clinically unacceptable.

Results: Using various comparison metrics (the mean surface distance, Hausdorff distance, and Dice similarity coefficient) for the 2 sets of beam apertures, we found that treatment beam apertures rated acceptable had significantly better agreement with the verification beam apertures than those rated unacceptable (P < .01). Upon receiver operating characteristic analysis, we found the area under the curve for all metrics to be 0.89 to 0.95, which demonstrated the high sensitivity and specificity of our quality verification technique.

Conclusions: We found that our technique of automatically verifying the beam aperture is an effective tool for flagging potentially unacceptable beam apertures during the treatment plan review process. Accordingly, we will clinically deploy this quality verification technique as part of a fully automated treatment planning tool and automated plan quality assurance program.
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http://dx.doi.org/10.1016/j.prro.2020.05.001DOI Listing
May 2020

Incidence of and risk factors for late cholecystectomy in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Eur J Cancer 2020 07 15;133:4-13. Epub 2020 May 15.

Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Paediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Background: Gallbladder disease and need for cholecystectomy are common and significant contributors to patient morbidity and healthcare costs. Childhood cancer survivors are at elevated risk for developing cholelithiasis. However, their incidence of and risk factors for late (>5 years from diagnosis) cholecystectomy have not been studied.

Methods: A total of 25,549 survivors (median age at diagnosis 6.9 years, range 0-21.0; current age 30.7 years, range 5.6-65.9) diagnosed between 1970 and 1999 and 5037 siblings were queried for self-reported cholecystectomy occurring five or more years from primary cancer diagnosis. Piecewise exponential models evaluated associations between cancer treatment exposures and late cholecystectomy.

Results: Over a median follow-up period of 21.9 and 26.0 years, respectively, 789 survivors and 168 siblings underwent late cholecystectomy (cumulative incidence 7.2%, 95% confidence interval [CI] = 6.5-7.8% and 6.6%, 95% CI = 5.4-7.6%, respectively; rate ratio [RR] = 1.3, 95% CI = 1.1-1.5). Compared with siblings, survivors of acute lymphoblastic leukaemia (RR = 1.4, 95% CI = 1.2-1.8), soft tissue sarcoma (RR = 1.4, 95% CI = 1.0-1.8) and bone cancer (RR = 1.3, 95% CI = 1.0-1.8) were at the greatest risk. In addition to attained age, female sex and increasing body mass index, exposure to high-dose (≥750 mg/m) platinum chemotherapy (RR = 2.6, 95% CI = 1.5-4.5), vinca alkaloid chemotherapy (RR = 1.4, 95% CI = 1.1-1.8) or total body irradiation (TBI; RR = 2.2, 95% CI = 1.2-4.2) were each associated with late cholecystectomy.

Conclusions: Independent of traditional risk factors for gallbladder disease, exposure to high-dose platinum chemotherapy, vinca alkaloid chemotherapy or TBI increased risk for late cholecystectomy. These findings should inform current long-term follow-up guidelines and education regarding risk for late cholecystectomy.
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http://dx.doi.org/10.1016/j.ejca.2020.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365349PMC
July 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

Longitudinal pain and pain interference in long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Cancer 2020 Jun 30;126(12):2915-2923. Epub 2020 Mar 30.

Department of Psychology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: The objective of this study was to characterize the prevalence and risk of pain, pain interference, and recurrent pain in adult survivors of childhood cancer in comparison with siblings.

Methods: This study analyzed longitudinal data from survivors (n = 10,012; 48.7% female; median age, 31 years [range, 17-57 years]; median time since diagnosis, 23 years) and siblings (n = 3173) from the Childhood Cancer Survivor Study. Survivors were diagnosed between 1970 and 1986 at 1 of 26 participating sites. Associations between risk factors (demographics, cancer-related factors, and psychological symptoms) and pain, pain interference, and recurrent pain (5 years apart) were assessed with multinomial logistic regression. Path analyses examined cross-sectional associations between risk factors and pain outcomes.

Results: Twenty-nine percent of survivors reported moderate to severe pain, 20% reported moderate to extreme pain interference, and 9% reported moderate to severe recurrent pain. Female sex, a sarcoma/bone tumor diagnosis, and severe/life-threatening chronic medical conditions were associated with recurrent pain. Depression and anxiety were associated with increased risk for all pain outcomes. Poor vitality mediated the effects of anxiety on high pain and pain interference (root mean square error of approximation, 0.002).

Conclusions: A large proportion of adult survivors report moderate to severe pain and pain interference more than 20 years after their diagnosis. Increased screening and early intervention for pain interference and recurrent pain are warranted.
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http://dx.doi.org/10.1002/cncr.32853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245551PMC
June 2020

A Mail Audit Independent Peer Review System for Dosimetry Verification of a Small Animal Irradiator.

Radiat Res 2020 04 18;193(4):341-350. Epub 2020 Feb 18.

Departments of Radiation Physics.

Dedicated precision orthovoltage small animal irradiators have become widely available in the past decade and are commonly used for radiation biology research. However, there is a lack of dosimetric standardization among these irradiators, which affects the reproducibility of radiation-based animal studies. The purpose of this study was to develop a mail-based, independent peer review system to verify dose delivery among institutions using X-RAD 225Cx irradiators (Precision X-Ray, North Branford, CT). A robust, user-friendly mouse phantom was constructed from high-impact polystyrene and designed with dimensions similar to those of a typical laboratory mouse. The phantom accommodates three thermoluminescent dosimeters (TLDs) to measure dose. The mouse peer review system was commissioned in a small animal irradiator using anterior-posterior and posterior-anterior beams of 225 kVp and then mailed to three institutions to test the feasibility of the audit service. The energy correction factor for TLDs in the mouse phantom was derived to validate the delivered dose using this particular animal irradiation system. This feasibility study indicated that three institutions were able to deliver a radiation dose to the mouse phantom within ±10% of the target dose. The developed mail audit independent peer review system for the verification of mouse dosimetry can be expanded to characterize other commercially available orthovoltage irradiators, thereby enhancing the reproducibility of studies employing these irradiators.
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http://dx.doi.org/10.1667/RR15220.1DOI Listing
April 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

Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort.

BMJ 2020 01 15;368:l6794. Epub 2020 Jan 15.

Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA.

Objective: To investigate the impact of modifications to contemporary cancer protocols, which minimize exposures to cardiotoxic treatments and preserve long term health, on serious cardiac outcomes among adult survivors of childhood cancer.

Design: Retrospective cohort study.

Setting: 27 institutions participating in the Childhood Cancer Survivor Study.

Participants: 23 462 five year survivors (6193 (26.4%) treated in the 1970s, 9363 (39.9%) treated in the 1980s, and 7906 (33.6%) treated in the 1990s) of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft tissue sarcomas, and bone sarcomas diagnosed prior to age 21 years between 1 January 1970 and 31 December 1999. Median age at diagnosis was 6.1 years (range 0-20.9) and 27.7 years (8.2-58.3) at last follow-up. A comparison group of 5057 siblings of cancer survivors were also included.

Main Outcome Measures: Cumulative incidence and 95% confidence intervals of reported heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias by treatment decade. Events were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events. Multivariable subdistribution hazard models were used to estimate hazard ratios by decade, and mediation analysis examined risks with and without exposure to cardiotoxic treatments.

Results: The 20 year cumulative incidence of heart failure (0.69% for those treated in the 1970s, 0.74% for those treated in the 1980s, 0.54% for those treated in the 1990s) and coronary artery disease (0.38%, 0.24%, 0.19%, respectively), decreased in more recent eras (P<0.01), though not for valvular disease (0.06%, 0.06%, 0.05%), pericardial disease (0.04%, 0.02%, 0.03%), or arrhythmias (0.08%, 0.09%, 0.13%). Compared with survivors with a diagnosis in the 1970s, the risk of heart failure, coronary artery disease, and valvular heart disease decreased in the 1980s and 1990s but only significantly for coronary artery disease (hazard ratio 0.65, 95% confidence interval 0.45 to 0.92 and 0.53, 0.36 to 0.77, respectively). The overall risk of coronary artery disease was attenuated by adjustment for cardiac radiation (0.90, 0.78 to 1.05), particularly among survivors of Hodgkin lymphoma (unadjusted for radiation: 0.77, 0.66 to 0.89; adjusted for radiation: 0.87, 0.69 to 1.10).

Conclusions: Historical reductions in exposure to cardiac radiation have been associated with a reduced risk of coronary artery disease among adult survivors of childhood cancer. Additional follow-up is needed to investigate risk reductions for other cardiac outcomes.

Trial Registration: ClinicalTrials.gov NCT01120353.
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http://dx.doi.org/10.1136/bmj.l6794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190022PMC
January 2020

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

Comparison of Radiation Dose Reconstruction Methods to Investigate Late Adverse Effects of Radiotherapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

Radiat Res 2020 02 3;193(2):95-106. Epub 2019 Dec 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Quantification of radiation dose to normal tissue during radiotherapy is critical for assessing risk for radiotherapy-related late effects, including subsequent neoplasms (SNs). Case-control studies of SNs typically reconstruct absorbed radiation dose to the specific SN location using individual treatment parameters. A simplified method estimates the maximum prescribed target dose to the body region in which the SN arises. We compared doses and risk estimates from these methods using data from case-control studies of subsequent brain tumors (64 cases, 244 controls) and breast cancer (94 cases, 358 controls) nested within the Childhood Cancer Survivor Study (≥5-year survivors of childhood cancer diagnosed 1970-1986). The weighted kappa statistic [95% confidence interval (CI)] evaluating agreement between categorical (>0-9.9/10-19.9/20-29.9/≥30 Gy) body-region and tumor location-specific doses was 0.95 (0.91-0.98) for brain and 0.76 (0.69-0.82) for breast. The body-region and location-specific doses were assigned to the same dose category for a smaller proportion of patients treated with fields delivering a heterogeneous dose across the tissue of interest (e.g., partial brain field = 57.1%; mantle field = 61.3%) than patients treated with fields delivering a more homogeneous dose (e.g., whole brain field = 100%). Excess odds ratios per Gy (95% CI) from conditional logistic regression were 1.25 (0.33-6.33) and 1.20 (0.31-6.14) for brain tumors and 0.21 (0.05-0.77) and 0.10 (0.02-0.44) for breast cancer, using location-specific and body-region doses, respectively. We observed that body-region doses can approximate location-specific doses when the tissue of interest is clearly in the radiation field or outside the treated body region. Agreement is lower when there is greater ambiguity of SN location relative to the treatment field.
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http://dx.doi.org/10.1667/RR15308.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063664PMC
February 2020

Reference dataset of users' photon beam modeling parameters for the Eclipse, Pinnacle, and RayStation treatment planning systems.

Med Phys 2020 Jan 15;47(1):282-288. Epub 2019 Nov 15.

Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Purpose: The aim of this work was to provide a novel description of how the radiotherapy community configures treatment planning system (TPS) radiation beam models for clinically used treatment machines. Here we describe the results of a survey of self-reported TPS beam modeling parameter values across different C-arm linear accelerators, beam energies, and multileaf collimator (MLC) configurations.

Acquisition And Validation Methods: Beam modeling data were acquired via electronic survey implemented through the Imaging and Radiation Oncology Core (IROC) Houston Quality Assurance Center's online facility questionnaire. The survey was open to participation from January 2018 through January 2019 for all institutions monitored by IROC. After quality control, 2818 beam models were collected from 642 institutions. This survey, designed for Eclipse, Pinnacle, and RayStation, instructed physicists to report parameter values used to model the radiation source and MLC for each treatment machine and beam energy used clinically for intensity-modulated radiation therapy. Parameters collected included the effective source/spot size, MLC transmission, dosimetric leaf gap, tongue and groove effect, and other nondosimetric parameters specific to each TPS. To facilitate survey participation, instructions were provided on how to identify requested beam modeling parameters within each TPS environment.

Data Format And Usage Notes: Numeric values of the beam modeling parameters are compiled and tabulated according to TPS and calculation algorithm, linear accelerator model class, beam energy, and MLC configuration. Values are also presented as distributions, ranging from the 2.5th to the 97.5th percentile.

Potential Applications: These data provide an independent guide describing how the radiotherapy community mathematically represents its clinical radiation beams. These distributions may be used by the community for comparison during the commissioning or verification of their TPS beam models. Ultimately, we hope that the current work will allow institutions to spot potentially suspicious parameter values and help ensure more accurate radiotherapy delivery.
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http://dx.doi.org/10.1002/mp.13892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980266PMC
January 2020

Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use: A Report From the Childhood Cancer Survivor Study.

JAMA Pediatr 2019 Oct 28. Epub 2019 Oct 28.

Radiation Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, Maryland.

Importance: Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied.

Objectives: To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status.

Design, Setting, And Participants: In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018.

Exposures: Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents.

Main Outcomes And Measures: Odds ratios (ORs) for subsequent breast cancer by ER status.

Results: A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use.

Conclusions And Relevance: This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.
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http://dx.doi.org/10.1001/jamapediatrics.2019.3807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820042PMC
October 2019