Impact of risk-based therapy on late morbidity and mortality in neuroblastoma survivors: a report from the Childhood Cancer Survivor Study.

BACKGROUND: Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences has not been well described. METHODS: Late mortality, subsequent malignant neoplasms (SMNs), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year Childhood Cancer Survivor Study (CCSS) survivors of neuroblastoma diagnosed 1987-1999. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n = 425]; intermediate [n = 252]; high [n = 245]). Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) of SMNs were compared with matched population controls. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals for CHC compared with 1029 CCSS siblings. RESULTS: Among survivors (49.8% male; median age = 21 years, range = 7-42; median follow-up = 19.3 years, range = 5-29.9), 80% with low-risk disease were treated with surgery alone, whereas 79.1% with high-risk disease received surgery, radiation, chemotherapy ± autologous stem cell transplant (ASCT). All-cause mortality was elevated across risk groups (SMRhigh = 27.7 [21.4-35.8]; SMRintermediate = 3.3 [1.7-6.5]; SMRlow = 2.8 [1.7-4.8]). SMN risk was increased among high- and intermediate-risk survivors (SIRhigh = 28.0 [18.5-42.3]; SIRintermediate = 3.7 [1.2-11.3]) but did not differ from the US population for survivors of low-risk disease. Compared with siblings, survivors had an increased risk of grade 3-5 CHCs, particularly among those with high-risk disease (HRhigh = 16.1 [11.2-23.2]; HRintermediate = 6.3 [3.8-10.5]; HRlow = 1.8 [1.1-3.1]). CONCLUSION: Survivors of high-risk disease treated in the early days of risk stratification carry a markedly elevated burden of late recurrence, SMN, and organ-related multimorbidity, whereas survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes.

Trends in Radiation Dose to the Contralateral Breast During Breast Cancer Radiation Therapy.

Over 4 million survivors of breast cancer live in the United States, 35% of whom were treated before 2009. Approximately half of patients with breast cancer receive radiation therapy, which exposes the untreated contralateral breast to radiation and increases the risk of a subsequent contralateral breast cancer (CBC). Radiation oncology has strived to reduce unwanted radiation dose, but it is unknown whether a corresponding decline in actual dose received to the untreated contralateral breast has occurred. The purpose of this study was to evaluate trends in unwanted contralateral breast radiation dose to inform risk assessment of second primary cancer in the contralateral breast for long-term survivors of breast cancer. Individually estimated radiation absorbed doses to the four quadrants and areola central area of the contralateral breast were estimated for 2,132 women treated with radiation therapy for local/regional breast cancers at age <55 years diagnosed between 1985 and 2008. The two inner quadrant doses and two outer quadrant doses were averaged. Trends in dose to each of the three areas of the contralateral breast were evaluated in multivariable models. The population impact of reducing contralateral breast dose on the incidence of radiation-associated CBC was assessed by estimating population attributable risk fraction (PAR) in a multivariable model. The median dose to the inner quadrants of the contralateral breast was 1.70 Gy; to the areola, 1.20 Gy; and to the outer quadrants, 0.72 Gy. Ninety-two percent of patients received ≥1 Gy to the inner quadrants. For each calendar year of diagnosis, dose declined significantly for each location, most rapidly for the inner quadrants (0.04 Gy/year). Declines in dose were similar across subgroups defined by age at diagnosis and body mass index. The PAR for CBC due to radiation exposure >1 Gy for women <40 years of age was 17%. Radiation dose-reduction measures have reduced dose to the contralateral breast during breast radiation therapy. Reducing the dose to the contralateral breast to <1 Gy could prevent an estimated 17% of subsequent radiation-associated CBCs for women treated under 40 years of age. These dose estimates inform CBC surveillance for the growing number of breast cancer survivors who received radiation therapy as young women in recent decades. Continued reductions in dose to the contralateral breast could further reduce the incidence of radiation-associated CBC.

Cardiac Substructure Radiation Dose and Risk of Late Cardiac Disease in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.

PURPOSE: Radiation-associated cardiac disease is a major cause of morbidity/mortality among childhood cancer survivors. Radiation dose-response relationships for cardiac substructures and cardiac diseases remain unestablished. METHODS: Using the 25,481 5-year survivors of childhood cancer treated from 1970 to 1999 in the Childhood Cancer Survivor Study, we evaluated coronary artery disease (CAD), heart failure (HF), valvular disease (VD), and arrhythmia. We reconstructed radiation doses for each survivor to the coronary arteries, chambers, valves, and whole heart. Excess relative rate (ERR) models and piecewise exponential models evaluated dose-response relationships. RESULTS: The cumulative incidence 35 years from diagnosis was 3.9% (95% CI, 3.4 to 4.3) for CAD, 3.8% (95% CI, 3.4 to 4.2) for HF, 1.2% (95% CI, 1.0 to 1.5) for VD, and 1.4% (95% CI, 1.1 to 1.6) for arrhythmia. A total of 12,288 survivors (48.2%) were exposed to radiotherapy. Quadratic ERR models improved fit compared with linear ERR models for the dose-response relationship between mean whole heart and CAD, HF, and arrhythmia, suggesting a potential threshold dose; however, such departure from linearity was not observed for most cardiac substructure end point dose-response relationships. Mean doses of 5-9.9 Gy to the whole heart did not increase the risk of any cardiac diseases. Mean doses of 5-9.9 Gy to the right coronary artery (rate ratio [RR], 2.6 [95% CI, 1.6 to 4.1]) and left ventricle (RR, 2.2 [95% CI, 1.3 to 3.7]) increased risk of CAD, and to the tricuspid valve (RR, 5.5 [95% CI, 2.0 to 15.1]) and right ventricle (RR, 8.4 [95% CI, 3.7 to 19.0]) increased risk of VD. CONCLUSION: Among children with cancer, there may be no threshold dose below which radiation to the cardiac substructures does not increase the risk of cardiac diseases. This emphasizes their importance in modern treatment planning.

Late Health Outcomes Among Survivors of Wilms Tumor Diagnosed Over Three Decades: A Report From the Childhood Cancer Survivor Study.

PURPOSE: To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens. METHODS: Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents. RESULTS: Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity. CONCLUSION: With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

Long-Term Morbidity and Mortality Among Survivors of Neuroblastoma Diagnosed During Infancy: A Report From the Childhood Cancer Survivor Study.

PURPOSE: To describe the risk of late mortality, subsequent malignant neoplasms (SMNs), and chronic health conditions (CHCs) in survivors of neuroblastoma diagnosed in infancy by treatment era and exposures. METHODS: Among 5-year survivors of neuroblastoma in the Childhood Cancer Survivor Study diagnosed age < 1 year between 1970 and 1999, we examined the cumulative incidence of late (> 5 years from diagnosis) mortality, SMN, and CHCs (grades 2-5 and 3-5). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs by decade and treatment (surgery-alone v chemotherapy with or without surgery [C ± S] v radiation with or without chemotherapy ± surgery [R ± C ± S]) among survivors and between survivors and 5,051 siblings. RESULTS: Among 1,397 eligible survivors, the 25-year cumulative incidence of late mortality was 2.1% (95% CI, 1.3 to 3.9) with no difference by treatment era. Among 990 participants who completed a baseline survey, fewer survivors received radiation in more recent eras (51.2% 1970s, 20.4% 1980s, and 10.1% 1990s; P < .001). Risk of SMN was elevated only among individuals treated with radiation-containing regimens compared with surgery alone (HR[C ± S], 3.2 [95% CI, 0.9 to 11.6]; HR[R ± C ± S], 5.7 [95% CI, 1.2 to 28.1]). In adjusted models, there was a 50% reduction in risk of grade 3-5 CHCs in the 1990s versus 1970s (HR, 0.5 [95% CI, 0.3 to 0.9]; P = .01); individuals treated with radiation had a 3.6-fold risk for grade 3-5 CHCs (95% CI, 2.1 to 6.2) versus those treated with surgery alone. When compared with siblings, risk of grade 3-5 CHCs for survivors was lowest in the most recent era (HR[1970s], 4.7 [95% CI, 3.4 to 6.5]; HR[1980s], 4.6 [95% CI, 3.3 to 6.4]; HR[1990s], 2.5 [95% CI, 1.7 to 3.9]). CONCLUSION: Neuroblastoma survivors treated during infancy have a relatively low absolute burden of late mortality and SMN. Encouragingly, risk of CHCs has declined in more recent eras with reduced exposure to radiation therapy.

Minimally Invasive Esophagectomy Is Associated with Superior Survival Compared to Open Surgery.

INTRODUCTION: Minimally invasive esophagectomy (MIE) has not been associated with a long-term survival advantage compared to open esophagectomy (OE). We investigated survival differences between MIE, including laparoscopic and robotic, and OE. METHODS: Patients undergoing esophagectomy from 2010 to 2014 with T1-4N0-3M0, adenocarcinoma or squamous cell histology, in middle or lower esophagus were queried from the National Cancer Database and stratified into groups based on their surgical procedure: robotic, laparoscopic, or OE. Propensity matching (1:1) was done between robotic and laparoscopic to produce an MIE group. The MIE group was matched to OE yielding a 1:1:2 matching of robotic:laparoscopic:OE. Postoperative outcomes and survival (Kaplan-Meier) were compared between groups. RESULTS: Prior to matching, 7,163 patients met inclusion criteria and a greater portion underwent OE (67.7%) than MIE (laparoscopic 24.9% and robotic 7.4%). Matching yielded similar groups (robotic = 527, laparoscopic = 527, and OE =1054). Compared to OE, MIE patients had a significantly greater number of nodes sampled and trended toward increased R0 resections (96.1% vs 94.3%, P = .053). OE was associated with a longer median postoperative stay (10 vs 9 days, P = .001). Mortality at 30 and 90 days was similar. However, postoperative survival for MIE was significantly greater than OE (P < .001). No survival difference existed between robotic and laparoscopic (P = .723). CONCLUSIONS: MIE is associated with increased number of nodes examined and a shorter postoperative length of stay. After propensity matching, patients undergoing MIE had better long but not short-term survival than OE. This benefit seems to be independent of the use of robotic technology.

Health Benefits and Cost-Effectiveness of Children's Oncology Group Breast Cancer Screening Guidelines for Chest-Irradiated Hodgkin Lymphoma Survivors.

PURPOSE: To evaluate the outcomes and cost-effectiveness of the Children's Oncology Group Guideline recommendation for breast cancer (BC) screening using mammography (MAM) and breast magnetic resonance imaging (MRI) in female chest-irradiated childhood Hodgkin lymphoma (HL) survivors. Digital breast tomosynthesis (DBT), increasingly replacing MAM in practice, was also examined. METHODS: Life years (LYs), quality-adjusted LYs (QALYs), BC mortality, health care costs, and false-positive screen frequencies of undergoing annual MAM, DBT, MRI, MAM + MRI, and DBT + MRI from age 25 to 74 years were estimated by microsimulation. BC risks and non-BC mortality were estimated from female 5-year survivors of HL in the Childhood Cancer Survivor Study and the US population. Test performance of MAM and MRI was synthesized from HL studies, and that of DBT from the general population. Costs (2017 US dollars [USD]) and utility weights were obtained from the medical literature. Incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: With 100% screening adherence, annual BC screening extended LYs by 0.34-0.46 years over no screening. If the willingness-to-pay threshold to gain a quality-adjusted LY was ICER < $100,000 USD, annual MAM at age 25-74 years was the only cost-effective strategy. When nonadherence was taken into consideration, only annual MAM at age 30-74 years (ICER = $56,972 USD) was cost-effective. Supplementing annual MAM with MRI costing $545 USD was not cost-effective under either adherence condition. If MRI costs were reduced to $300 USD, adding MRI to annual MAM at age 30-74 years could become more cost-effective, particularly in the reduced adherence condition (ICER = $133,682 USD). CONCLUSION: Annual BC screening using MAM at age 30-74 years is effective and cost-effective in female chest-irradiated HL survivors. Although annual adjunct MRI is not cost-effective at $545 USD cost, it could become cost-effective as MRI cost is reduced, a plausible scenario with the emergent use of abbreviated MRI.

Association of Changes in Cancer Therapy Over 3 Decades With Risk of Subsequent Breast Cancer Among Female Childhood Cancer Survivors: A Report From the Childhood Cancer Survivor Study (CCSS).

Importance: Breast cancer is the most common invasive subsequent malignant disease in childhood cancer survivors, though limited data exist on changes in breast cancer rates as primary cancer treatments have evolved. Objective: To quantify the association between temporal changes in cancer treatment over 3 decades and subsequent breast cancer risk. Design, Setting, and Participants: Retrospective cohort study of 5-year cancer survivors diagnosed when younger than 21 years between 1970 and 1999, with follow-up through December 5, 2020. Exposures: Radiation and chemotherapy dose changes over time. Main Outcomes and Measures: Breast cancer cumulative incidence rates and age-specific standardized incidence ratios (SIRs) compared across treatment decades (1970-1999). Piecewise exponential models estimated invasive breast cancer and ductal carcinoma in situ (DCIS) risk and associations with treatment exposures, adjusted for age at childhood cancer diagnosis and attained age. Results: Among 11 550 female survivors (median age, 34.2 years; range 5.6-66.8 years), 489 developed 583 breast cancers: 427 invasive, 156 DCIS. Cumulative incidence was 8.1% (95% CI, 7.3%-9.0%) by age 45 years. An increased breast cancer risk (SIR, 6.6; 95% CI, 6.1-7.2) was observed for survivors compared with the age-sex-calendar-year-matched general population. Changes in therapy by decade included reduced rates of chest (34% in the 1970s, 22% in the 1980s, and 17% in the 1990s) and pelvic radiotherapy (26%, 17%, and 13% respectively) and increased rates of anthracycline chemotherapy exposures (30%, 51%, and 64%, respectively). Adjusting for age and age at diagnosis, the invasive breast cancer rate decreased 18% every 5 years of primary cancer diagnosis era (rate ratio [RR], 0.82; 95% CI, 0.74-0.90). When accounting for chest radiotherapy exposure, the decline attenuated to an 11% decrease every 5 years (RR, 0.89; 95% CI, 0.81-0.99). When additionally adjusted for anthracycline dose and pelvic radiotherapy, the decline every 5 years increased to 14% (RR, 0.86; 95% CI, 0.77-0.96). Although SIRs of DCIS generally increased over time, there were no statistically significant changes in incidence. Conclusions and Relevance: Invasive breast cancer rates in childhood cancer survivors have declined with time, especially in those younger than 40 years. This appears largely associated with the reduced use of chest radiation therapy, but was tempered by concurrent changes in other therapies.

Validation and Comparison of Radiograph-Based Organ Dose Reconstruction Approaches for Wilms Tumor Radiation Treatment Plans.

Purpose: Our purpose was to validate and compare the performance of 4 organ dose reconstruction approaches for historical radiation treatment planning based on 2-dimensional radiographs. Methods and Materials: We considered 10 patients with Wilms tumor with planning computed tomography images for whom we developed typical historic Wilms tumor radiation treatment plans, using anteroposterior and posteroanterior parallel-opposed 6 MV flank fields, normalized to 14.4 Gy. Two plans were created for each patient, with and without corner blocking. Regions of interest (lungs, heart, nipples, liver, spleen, contralateral kidney, and spinal cord) were delineated, and dose-volume metrics including organ mean and minimum dose (Dmean and Dmin) were computed as the reference baseline for comparison. Dosimetry for the 20 plans was then independently reconstructed using 4 different approaches. Three approaches involved surrogate anatomy, among which 2 used demographic-matching criteria for phantom selection/building, and 1 used machine learning. The fourth approach was also machine learning-based, but used no surrogate anatomies. Absolute differences in organ dose-volume metrics between the reconstructed and the reference values were calculated. Results: For Dmean and Dmin (average and minimum point dose) all 4 dose reconstruction approaches performed within 10% of the prescribed dose (≤1.4 Gy). The machine learning-based approaches showed a slight advantage for several of the considered regions of interest. For Dmax (maximum point dose), the absolute differences were much higher, that is, exceeding 14% (2 Gy), with the poorest agreement observed for near-beam and out-of-beam organs for all approaches. Conclusions: The studied approaches give comparable dose reconstruction results, and the choice of approach for cohort dosimetry for late effects studies should still be largely driven by the available resources (data, time, expertise, and funding).

Development and validation of a population-based anatomical colorectal model for radiation dosimetry in late effects studies of survivors of childhood cancer.

PURPOSE: The purposes of this study were to develop and integrate a colorectal model that incorporates anatomical variations of pediatric patients into the age-scalable MD Anderson Late Effects (MDA-LE) computational phantom, and validate the model for pediatric radiation therapy (RT) dose reconstructions. METHODS: Colorectal contours were manually derived from whole-body non-contrast computed tomography (CT) scans of 114 pediatric patients (age range: 2.1-21.6 years, 74 males, 40 females). One contour was used for an anatomical template, 103 for training and 10 for testing. Training contours were used to create a colorectal principal component analysis (PCA)-based statistical shape model (SSM) to extract the population's dominant deformations. The SSM was integrated into the MDA-LE phantom. Geometric accuracy was assessed between patient-specific and SSM contours using several overlap metrics. Two alternative colorectal shapes were generated using the first 17 dominant modes of the PCA-based SSM. Dosimetric accuracy was assessed by comparing colorectal doses from test patients' CT-based RT plans (ground truth) with reconstructed doses for the mean and two alternative models in age-matched MDA-LE phantoms. RESULTS: When using all 103 PCA modes, the mean (min-max) Dice similarity coefficient, distance-to-agreement and Hausdorff distance between the patient-specific and reconstructed contours for the test patients were 0.89 (0.85-0.91), 2.1 mm (1.7-3.0), and 8.6 mm (5.7-14.3), respectively. The average percent difference between reconstructed and ground truth mean and maximum colorectal doses for the mean (alternative 1, 2) model were 6.3% (8.1%, 6.1%) and 4.4% (4.3%, 4.7%), respectively. CONCLUSIONS: We developed, validated and integrated a colorectal PCA-based SSM into the MDA-LE phantom and demonstrated its dosimetric performance for accurate pediatric RT dose reconstruction.

Body region-specific 3D age-scaling functions for scaling whole-body computed tomography anatomy for pediatric late effects studies.

Purpose.Radiation epidemiology studies of childhood cancer survivors treated in the pre-computed tomography (CT) era reconstruct the patients' treatment fields on computational phantoms. For such studies, the phantoms are commonly scaled to age at the time of radiotherapy treatment because age is the generally available anthropometric parameter. Several reference size phantoms are used in such studies, but reference size phantoms are only available at discrete ages (e.g.: newborn, 1, 5, 10, 15, and Adult). When such phantoms are used for RT dose reconstructions, the nearest discrete-aged phantom is selected to represent a survivor of a specific age. In this work, we (1) conducted a feasibility study to scale reference size phantoms at discrete ages to various other ages, and (2) evaluated the dosimetric impact of using exact age-scaled phantoms as opposed to nearest age-matched phantoms at discrete ages.Methods.We have adopted the University of Florida/National Cancer Institute (UF/NCI) computational phantom library for our studies. For the feasibility study, eight male and female reference size UF/NCI phantoms (5, 10, 15, and 35 years) were downscaled to fourteen different ages which included next nearest available lower discrete ages (1, 5, 10 and 15 years) and the median ages at the time of RT for Wilms' tumor (3.9 years), craniospinal (8.0 years), and all survivors (9.1 years old) in the Childhood Cancer Survivor Study (CCSS) expansion cohort treated with RT. The downscaling was performed using our in-house age scaling functions (ASFs). To geometrically validate the scaling, Dice similarity coefficient (DSC), mean distance to agreement (MDA), and Euclidean distance (ED) were calculated between the scaled and ground-truth discrete-aged phantom (unscaled UF/NCI) for whole-body, brain, heart, liver, pancreas, and kidneys. Additionally, heights of the scaled phantoms were compared with ground-truth phantoms' height, and the Centers for Disease Control and Prevention (CDC) reported 50th percentile height. Scaled organ masses were compared with ground-truth organ masses. For the dosimetric assessment, one reference size phantom and seventeen body-size dependent 5-year-old phantoms (9 male and 8 female) of varying body mass indices (BMI) were downscaled to 3.9-year-old dimensions for two different radiation dose studies. For the first study, we simulated a 6 MV photon right-sided flank field RT plan on a reference size 5-year-old and 3.9-year-old (both of healthy BMI), keeping the field size the same in both cases. Percent of volume receiving dose ≥15 Gy (V15) and the mean dose were calculated for the pancreas, liver, and stomach. For the second study, the same treatment plan, but with patient anatomy-dependent field sizes, was simulated on seventeen body-size dependent 5- and 3.9-year-old phantoms with varying BMIs. V15, mean dose, and minimum dose received by 1% of the volume (D1), and by 95% of the volume (D95) were calculated for pancreas, liver, stomach, left kidney (contralateral), right kidney, right and left colons, gallbladder, thoracic vertebrae, and lumbar vertebrae. A non-parametric Wilcoxon rank-sum test was performed to determine if the dose to organs of exact age-scaled and nearest age-matched phantoms were significantly different (p < 0.05).Results.In the feasibility study, the best DSCs were obtained for the brain (median: 0.86) and whole-body (median: 0.91) while kidneys (median: 0.58) and pancreas (median: 0.32) showed poorer agreement. In the case of MDA and ED, whole-body, brain, and kidneys showed tighter distribution and lower median values as compared to other organs. For height comparison, the overall agreement was within 2.8% (3.9 cm) and 3.0% (3.2 cm) of ground-truth UF/NCI and CDC reported 50th percentile heights, respectively. For mass comparison, the maximum percent and absolute differences between the scaled and ground-truth organ masses were within 31.3% (29.8 g) and 211.8 g (16.4%), respectively (across all ages). In the first dosimetric study, absolute difference up to 6% and 1.3 Gy was found for V15and mean dose, respectively. In the second dosimetric study, V15and mean dose were significantly different (p < 0.05) for all studied organs except the fully in-beam organs. D1and D95were not significantly different for most organs (p > 0.05).Conclusion.We have successfully evaluated our ASFs by scaling UF/NCI computational phantoms from one age to another age, which demonstrates the feasibility of scaling any CT-based anatomy. We have found that dose to organs of exact age-scaled and nearest aged-matched phantoms are significantly different (p < 0.05) which indicates that using the exact age-scaled phantoms for retrospective dosimetric studies is a better approach.

Smoking, Radiation Therapy, and Contralateral Breast Cancer Risk in Young Women.

Evidence is mounting that cigarette smoking contributes to second primary contralateral breast cancer (CBC) risk. Whether radiation therapy (RT) interacts with smoking to modify this risk is unknown. In this multicenter, individually matched, case-control study, we examined the association between RT, smoking, and CBC risk. The study included 1521 CBC cases and 2212 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2008 aged younger than 55 years. Absorbed radiation doses to contralateral breast regions were estimated with thermoluminescent dosimeters in tissue-equivalent anthropomorphic phantoms, and smoking history was collected by interview. Rate ratios (RRs) and 95% confidence intervals (CIs) for CBC risk were estimated by multivariable conditional logistic regression. There was no interaction between any measure of smoking with RT to increase CBC risk (eg, the interaction of continuous RT dose with smoking at first breast cancer diagnosis [ever/never]: RR = 1.00, 95% CI = 0.89 to 1.14; continuous RT dose with years smoked: RR = 1.00, 95% CI = 0.99 to 1.01; and continuous RT dose with lifetime pack-years: RR = 1.00, 95% CI = 0.99 to 1.01). There was no evidence that RT further increased CBC risk in young women with first primary breast cancer who were current smokers or had smoking history.

Coronary Artery Disease in Young Women After Radiation Therapy for Breast Cancer: The WECARE Study.

BACKGROUND: Radiation therapy (RT) for breast cancer increases risk of coronary artery disease (CAD). Women treated for left- vs right-sided breast cancer receive greater heart radiation exposure, which may further increase this risk. The risk of radiation-associated CAD specifically among younger breast cancer survivors is not well defined. OBJECTIVES: The purpose of this study was to report CAD risk among participants in the Women's Environmental Cancer and Radiation Epidemiology Study. METHODS: A total of 1,583 women who were <55 years of age when diagnosed with breast cancer between 1985 and 2008 completed a cardiovascular health questionnaire. Risk of radiation-associated CAD was evaluated by comparing women treated with left-sided RT with women treated with right-sided RT using multivariable Cox proportional hazards models. Effect modification by treatment and cardiovascular risk factors was examined. RESULTS: In total, 517 women who did not receive RT and 94 women who had a pre-existing cardiovascular disease diagnosis were excluded, leaving 972 women eligible for analysis. Their median follow-up time was 14 years (range 1-29 years). The 27.5-year cumulative incidences of CAD for women receiving left- vs right-sided RT were 10.5% and 5.8%, respectively (P = 0.010). The corresponding HR of CAD for left- vs right-sided RT in the multivariable Cox model was 2.5 (95% CI: 1.3-4.7). There was no statistically significant effect modification by any factor evaluated. CONCLUSIONS: Young women treated with RT for left-sided breast cancer had over twice the risk of CAD compared with women treated with RT for right-sided breast cancer. Laterality of RT is independently associated with an increased risk of CAD and should be considered in survivorship care of younger breast cancer patients.

Lung Cancer as a Subsequent Malignant Neoplasm in Survivors of Childhood Cancer.

BACKGROUND: Lung cancer, the most common cause of cancer-related death in adults, has not been well studied as a subsequent malignant neoplasm (SMN) in childhood cancer survivors. We assessed prevalence, risk factors, and outcomes for lung SMN in the Childhood Cancer Survivor Study (CCSS) cohort. METHODS: Among 25,654 5-year survivors diagnosed with childhood cancer (<21 years), lung cancer was self-reported and confirmed by pathology record review. Standardized incidence ratios (SIR) and cumulative incidences were calculated, comparing survivors to the general population, and hazard ratios (HR) were estimated using Cox regression for diagnosis and treatment exposures. RESULTS: Forty-two survivors developed a lung SMN [SIR, 4.0; 95% confidence interval (CI), 2.9-5.4] with a cumulative incidence of 0.16% at 30 years from diagnosis (95% CI, 0.09%-0.23%). In a treatment model, chest radiation doses of 10-30 Gy (HR, 3.4; 95% CI, 1.05-11.0), >30-40 Gy (HR, 4.6; 95% CI, 1.5-14.3), and >40 Gy (HR, 9.1; 95% CI, 3.1-27.0) were associated with lung SMN, with a monotone dose trend (P trend < 0.001). Survivors of Hodgkin lymphoma (SIR, 9.3; 95% CI, 6.2-13.4) and bone cancer (SIR, 4.4; 95% CI, 1.8-9.1) were at greatest risk for lung SMN. CONCLUSIONS: Survivors of childhood cancer are at increased risk for lung cancer compared with the general population. Greatest risk was observed among survivors who received chest radiotherapy or with primary diagnoses of Hodgkin lymphoma or bone cancer. IMPACT: This study describes the largest number of observed lung cancers in childhood cancer survivors and elucidates need for further study in this aging and growing population.

Radiation therapy related cardiac disease risk in childhood cancer survivors: Updated dosimetry analysis from the Childhood Cancer Survivor Study.

BACKGROUND AND PURPOSE: We previously evaluated late cardiac disease in long-term survivors in the Childhood Cancer Survivor Study (CCSS) based on heart radiation therapy (RT) doses estimated from an age-scaled phantom with a simple atlas-based heart model (HAtlas). We enhanced our phantom with a high-resolution CT-based anatomically realistic and validated age-scalable cardiac model (HHybrid). We aimed to evaluate how this update would impact our prior estimates of RT-related late cardiac disease risk in the CCSS cohort. METHODS: We evaluated 24,214 survivors from the CCSS diagnosed from 1970 to 1999. RT fields were reconstructed on an age-scaled phantom with HHybrid and mean heart dose (Dm), percent volume receiving ≥ 20 Gy (V20) and ≥ 5 Gy with V20 = 0 ( [Formula: see text] ) were calculated. We reevaluated cumulative incidences and adjusted relative rates of grade 3-5 Common Terminology Criteria for Adverse Events outcomes for any cardiac disease, coronary artery disease (CAD), and heart failure (HF) in association with Dm, V20, and [Formula: see text] (as categorical variables). Dose-response relationships were evaluated using piecewise-exponential models, adjusting for attained age, sex, cancer diagnosis age, race/ethnicity, time-dependent smoking history, diagnosis year, and chemotherapy exposure and doses. For relative rates, Dm was also considered as a continuous variable. RESULTS: Consistent with previous findings with HAtlas, reevaluation using HHybrid dosimetry found that, Dm ≥ 10 Gy, V20 ≥ 0.1%, and [Formula: see text]  ≥ 50% were all associated with increased cumulative incidences and relative rates for any cardiac disease, CAD, and HF. While updated risk estimates were consistent with previous estimates overall without statistically significant changes, there were some important and significant (P < 0.05) increases in risk with updated dosimetry for Dm in the category of 20 to 29.9 Gy and V20 in the category of 30% to 79.9%. When changes in the linear dose-response relationship for Dm were assessed, the slopes of the dose response were steeper (P < 0.001) with updated dosimetry. Changes were primarily observed among individuals with chest-directed RT with prescribed doses ≥ 20 Gy. CONCLUSION: These findings present a methodological advancement in heart RT dosimetry with improved estimates of RT-related late cardiac disease risk. While results are broadly consistent with our prior study, we report that, with updated cardiac dosimetry, risks of cardiac disease are significantly higher in two dose and volume categories and slopes of the Dm-specific RT-response relationships are steeper. These data support the use of contemporary RT to achieve lower heart doses for pediatric patients, particularly those requiring chest-directed RT.

Aortic root replacement with Medtronic Freestyle bioprosthesis: 25-year experience.

BACKGROUND: Stentless porcine bioprothesis is a surgical strategy to treat aortic root disease. Use has been limited due to the concern for long-term valve degeneration. This study evaluated the perioperative and late outcomes of patients with aortic root disease requiring root replacement. METHODS: A total of 409 patients underwent aortic root replacement by a single surgeon using a stentless porcine bioroot between February 1996 and May 2020. The cohort was divided into two groups (age ≤65 and >65 years). Descriptive statistics were used to analyze the data and Kaplan-Meier curves used to evaluate long-term outcomes. RESULTS: Patients age >65 years were more likely to be female (p = .01), have hypertension (p = .01), require circulatory arrest (p = .01), and have concomitant coronary artery bypass grafting (CABG) (p = .04). Baseline creatinine >1.8 (p = .20), diabetes (p = .06), and ejection fraction (p = .20) were similar between groups. The 1-, 5-, and 10-year survival for patients age ≤65 years were 92%, 87%, and 69%, respectively, significantly better than patients age >65 (88%, 73%, and 43%, respectively) (p < .01, Figure 1). The 1-, 5-, and 10-year freedom from reoperation for patients ≤65 years were 99%, 97%, and 93% versus 99%, 98%, and 96% in patients age >65 years, respectively (p = .24). CONCLUSION: Patients with aortic root disease can be treated with acceptable perioperative outcomes, long-term survival, and low reoperation rates using a stentless porcine bioprothesis. It should be considered irrespective of age due to its excellent durability and freedom from anti-coagulation requirement.

Late-onset kidney failure in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

BACKGROUND: The incidence of and risk factors for late-onset kidney failure among survivors over the very long term remains understudied. MATERIALS AND METHODS: A total of 25,530 childhood cancer survivors (median follow-up 22.3 years, interquartile range 17.4-28.8) diagnosed between 1970 and 1999, and 5045 siblings from the Childhood Cancer Survivor Study were assessed for self-reported late-onset kidney failure, defined as dialysis, renal transplantation, or death attributable to kidney disease. Piecewise exponential models evaluated associations between risk factors and the rate of late-onset kidney failure. RESULTS: A total of 206 survivors and 10 siblings developed late-onset kidney failure, a 35-year cumulative incidence of 1.7% (95% confidence interval [CI] = 1.4-1.9) and 0.2% (95% confidence interval [CI] = 0.1-0.4), respectively, corresponding to an adjusted rate ratio (RR) of 4.9 (95% CI = 2.6-9.2). High kidney dose from radiotherapy (≥15Gy; RR = 4.0, 95% CI = 2.1-7.4), exposure to high-dose anthracycline (≥250 mg/m2; RR = 1.6, 95% CI = 1.0-2.6) or any ifosfamide chemotherapy (RR = 2.6, 95% CI = 1.2-5.7), and nephrectomy (RR = 1.9, 95% CI = 1.0-3.4) were independently associated with elevated risk for late-onset kidney failure among survivors. Survivors who developed hypertension, particularly in the context of prior nephrectomy (RR = 14.4, 95% CI = 7.1-29.4 hypertension with prior nephrectomy; RR = 5.9, 95% CI = 3.3-10.5 hypertension without prior nephrectomy), or diabetes (RR = 2.2, 95%CI = 1.2-4.2) were also at elevated risk for late-onset kidney failure. CONCLUSIONS: Survivors of childhood cancer are at increased risk for late-onset kidney failure. Kidney dose from radiotherapy ≥15 Gy, high-dose anthracycline, any ifosfamide, and nephrectomy were associated with increased risk of late-onset kidney failure among survivors. Successful diagnosis and management of modifiable risk factors such as diabetes and hypertension may mitigate the risk for late-onset kidney failure. The association of late-onset kidney failure with anthracycline chemotherapy represents a novel finding that warrants further study.

Development and Validation of a Breast Cancer Risk Prediction Model for Childhood Cancer Survivors Treated With Chest Radiation: A Report From the Childhood Cancer Survivor Study and the Dutch Hodgkin Late Effects and LATER Cohorts.

PURPOSE: Women treated with chest radiation for childhood cancer have one of the highest risks of breast cancer. Models producing personalized breast cancer risk estimates applicable to this population do not exist. We sought to develop and validate a breast cancer risk prediction model for childhood cancer survivors treated with chest radiation incorporating treatment-related factors, family history, and reproductive factors. METHODS: Analyses were based on multinational cohorts of female 5-year survivors of cancer diagnosed younger than age 21 years and treated with chest radiation. Model derivation was based on 1,120 participants in the Childhood Cancer Survivor Study diagnosed between 1970 and 1986, with median attained age 42 years (range 20-64) and 242 with breast cancer. Model validation included 1,027 participants from three cohorts, with median age 32 years (range 20-66) and 105 with breast cancer. RESULTS: The model included current age, chest radiation field, whether chest radiation was delivered within 1 year of menarche, anthracycline exposure, age at menopause, and history of a first-degree relative with breast cancer. Ten-year risk estimates ranged from 2% to 23% for 30-year-old women (area under the curve, 0.63; 95% CI, 0.50 to 0.73) and from 5% to 34% for 40-year-old women (area under the curve, 0.67; 95% CI, 0.54 to 0.84). The highest risks were among premenopausal women older than age 40 years treated with mantle field radiation within a year of menarche who had a first-degree relative with breast cancer. It showed good calibration with an expected-to-observed ratio of the number of breast cancers of 0.92 (95% CI, 0.74 to 1.16). CONCLUSION: Breast cancer risk varies among childhood cancer survivors treated with chest radiation. Accurate risk prediction may aid in refining surveillance, counseling, and preventive strategies in this population.

Evaluation of disease staging and chemotherapeutic response in non-small cell lung cancer from patient tumor-derived metabolomic data.

OBJECTIVES: Despite extensive effort, the search for clinically-relevant metabolite biomarkers for early detection, disease monitoring, and outcome prediction in lung cancer remains unfulfilled. Although biofluid evaluation has been explored, the complexity inherent in metabolite data and the dynamic discrepancy between metabolites in biofluids vs. tumor tissue have prevented conclusive results. This proof-of-concept study explored models predictive of staging and chemotherapy response based on metabolomic analysis of fresh, patient-derived non-small cell lung cancer (NSCLC) core biopsies. MATERIALS AND METHODS: Samples (n = 36) were evaluated with high-resolution 2DLC-MS/MS and 13C-glucose enrichment, and the data were comprehensively analyzed with machine learning techniques. Patients were categorized as Disease-Control (DC) [encompassing complete-response (CR), partial-response (PR), and stable-disease (SD)] and Progressive-Disease (PD) in terms of first-line chemotherapy. Four major types of learning methods (partial least squares discriminant analysis (PLS-DA), support vector machines (SVM), artificial neural networks, and random forests (RF)) were applied to differentiate between positive (DC and CR/PR) and poor (PD and SD/PD) responses, and between stage I/II/III and stage IV disease. Models were trained with forward feature selection based on variable importance and tested on validation subsets. RESULTS: The models predicted patient classifications in the validation subsets with AUC (95 % CI): DC vs. PD (SVM), 0.970(0.961-0.979); CR/PR vs. SD/PD (PLS-DA), 0.880(0.865-0.895); stage I/II/III vs. IV (SVM), 0.902(0.880-0.924). Highest performing model was SVM for DC vs. PD (balanced accuracy = 0.92; kappa = 0.74). CONCLUSION: This study illustrates a comprehensive evaluation of patient tumor-specific metabolic profiles, with the potential to identify disease stage and predict response to first-line chemotherapy.