Presentation and outcome of subsequent thyroid cancer among childhood cancer survivors compared to sporadic thyroid cancer:a matched national study

Objective: Childhood cancer survivors (CCS) are at increased risk to develop differentiated thyroid cancer predominantly after radiotherapy (subsequent DTC). It is insufficiently known whether subsequent DTC in CCS has a different presentation or outcome than sporadic DTC. Methods: Patients with subsequent DTC (n = 31) were matched to patients with sporadic DTC (n = 93) on gender, age and year of diagnosis to compare presentation and DTC outcomes. Clinical data were collected retrospectively. Results: Among the CCS with subsequent DTC, all but one had received chemotherapy for their childhood cancer, 19 (61.3%) had received radiotherapy including the thyroid region, 3 (9.7%) 131I-MIBG and 8 (25.8%) had received treatment with chemotherapy only. Subsequent DTC was detected by surveillance through neck palpation (46.2%), as a self-identified mass (34.6%), or by chance. Among sporadic DTC patients, self detection predominated (68.8%). CCS with subsequent DTC tended to have on average smaller tumors (1.9 vs 2.4 cm, respectively, (P = 0.051), and more often bilateral (5/25 (60.0%) vs 28/92 (30.4%), P = 0.024). There were no significant differences in the occurrence of surgical complications, recurrence rate or disease-related death. Conclusion: When compared to patients with sporadic DTC, CCS with subsequent DTC seem to present with smaller tumors and more frequent bilateral tumors. Treatment outcome seems to be similar. The finding that one-third of subsequent DTC cases had been treated with chemotherapy only needs further investigation. These results are important for the development of surveillance programs for CCS at risk for DTC and for treatment guidelines of subsequent DTC

On the feasibility of automatically selecting similar patients in highly individualized radiotherapy dose reconstruction for historic data of pediatric cancer survivors

Purpose: The aim of this study is to establish the first step toward a novel and highly individualized three-dimensional (3D) dose distribution reconstruction method, based on CT scans and organ delineations of recently treated patients. Specifically, the feasibility of automatically selecting the CT scan of a recently treated childhood cancer patient who is similar to a given historically treated child who suffered from Wilms' tumor is assessed.Methods: A cohort of 37 recently treated children between 2- and 6-yr old are considered. Five potential notions of ground-truth similarity are proposed, each focusing on different anatomical aspects. These notions are automatically computed from CT scans of the abdomen and 3D organ delineations (liver, spleen, spinal cord, external body contour). The first is based on deformable image registration, the second on the Dice similarity coefficient, the third on the Hausdorff distance, the fourth on pairwise organ distances, and the last is computed by means of the overlap volume histogram. The relationship between typically available features of historically treated patients and the proposed ground-truth notions of similarity is studied by adopting state-of-the-art machine learning techniques, including random forest. Also, the feasibility of automatically selecting the most similar patient is assessed by comparing ground-truth rankings of similarity with predicted rankings.Results: Similarities (mainly) based on the external abdomen shape and on the pairwise organ distances are highly correlated (Pearson rp ≥ 0.70) and are successfully modeled with random forests based on historically recorded features (pseudo-R2 ≥ 0.69). In contrast, similarities based on the shape of internal organs cannot be modeled. For the similarities that random forest can reliably model, an estimation of feature relevance indicates that abdominal diameters and weight are the most important. Experiments on automatically selecting similar patients lead to coarse, yet quite robust results: the most similar patient is retrieved only 22% of the times, however, the error in worst-case scenarios is limited, with the fourth most similar patient being retrieved.Conclusions: Results demonstrate that automatically selecting similar patients is feasible when focusing on the shape of the external abdomen and on the position of internal organs. Moreover, whereas the common practice in phantom-based dose reconstruction is to select a representative phantom using age, height, and weight as discriminant factors for any treatment scenario, our analysis on abdominal tumor treatment for children shows that the most relevant features are weight and the anterior-posterior and left-right abdominal diameters

Relating anatomical variations and patient features with dose-reconstruction accuracy of a 3D dose-reconstruction approach using CT scans of recently-treated children

Purpose Reconstructing 3D dose distributions for pre-1990 pediatric 2D radiotherapy plans is challenging, but key to research on late adverse effects. We studied the relation between dosimetric accuracy, anatomical variation, and other patient features of a 3D dose-reconstruction approach using CT scans of recently-treated patients, rather than phantoms. Materials and methods CT-scans of 22 Wilms’ tumor patients (age:2.5-5.3yrs; n boys/girls:11/11) treated between 2004 and 2015 were included. Two clinical plans as applied to a 4-year-old boy and girl with a left-sided Wilms’ tumor served as references. Each plan was applied to the CT scans of the other 21 patients, adjusted to correct for anatomical differences as visible in digitally-reconstructed-radiographs, and the resulting dose was calculated. Deviations in reconstructed dose, with respect to the reference dose, in organs-at-risk (spinal cord, right kidney, liver, and spleen) were characterized by the mean dose error normalized by the prescribed dose (DEmean). Deviations in organs’ location relative to a reference point (\Delta O_loc) and in organs’ shape captured by the Dice coefficient (DC) were calculated. We estimated the Pearson’s correlation between DEmean, on the one hand, and O­loc, DC, gender, age, height, and weight, on the other hand. Results Average(range) DEmean values were: spinal cord:3(0-8)%; right kidney:6(0-20)%; liver:9(0-20)%; and spleen:23(0-80)%. DC and DEmean in the right kidney were moderately negatively correlated (r2=0.41). DEmean in the liver was uncorrelated with any o

Risk, risk factors and surveillance of subsequent malignant neoplasms in childhood cancer survivors: a review

Subsequent malignant neoplasms (SMNs) in childhood cancer survivors cause substantial morbidity and mortality. This review summarizes recent literature on SMN epidemiology, risk factors, surveillance, and interventions. Survivors of childhood cancer experience long-term increased SMN risk compared with the general population, with a greater than twofold increased solid tumor risk extending beyond age 40 years. There is a dose-dependent increased risk for solid tumors after radiotherapy, with the highest risks for tumors occurring in or near the treatment field (eg, greater than fivefold increased risk for breast, brain, thyroid, skin, bone, and soft tissue malignancies). Alkylating and anthracycline chemotherapies increase the risk for development of several solid malignancies in addition to acute leukemia/myelodysplasia, and these risks may be modified by other patient characteristics, such as age at exposure and, potentially, inherited genetic susceptibility. Strategies for identifying survivors at risk and initiating long-term surveillance have improved and interventions are underway to improve knowledge about late-treatment effects among survivors and caregivers. Better understanding of treatment-related risk factors and genetic susceptibility holds promise for refining surveillance strategies and, ultimately, upfront cancer therapies

The Dutch LATER physical outcomes set for self-reported data in survivors of childhood cancer

Purposes: Studies investigating self-reported long-term morbidity in childhood cancer survivors (CCS) are using heterogeneous outcome definitions, which compromises comparability and include (un)treated asymptomatic and symptomatic outcomes. We generated a Dutch LATER core set of clinically relevant physical outcomes, based on self-reported data. Clinically relevant outcomes were defined as outcomes associated with clinical symptoms or requiring medical treatment. Methods: First, we generated a draft outcome set based on existing questionnaires embedded in the Childhood Cancer Survivor Study, British Childhood Cancer Survivor Study, and Dutch LATER study. We added specific outcomes reported by survivors in the Dutch LATER questionnaire. Second, we selected a list of clinical relevant outcomes by agreement among a Dutch LATER experts team. Third, we compared the proposed clinically relevant outcomes to the severity grading of the Common Terminology Criteria for Adverse Events (CTCAE). Results: A core set of 74 self-reported long-term clinically relevant physical morbidity outcomes was established. Comparison to the CTCAE showed that 36% of these clinically relevant outcomes were missing in the CTCAE. Implications for Cancer Survivors: This proposed core outcome set of clinical relevant outcomes for self-reported data will be used to investigate the self-reported morbidity in the Dutch LATER study. Furthermore, this Dutch LATER outcome set can be used as a starting point for international harmonization for long-term outcomes in survivors of childhood cancer

Clinical characteristics and survival patterns of subsequent sarcoma, breast cancer, and melanoma after childhood cancer in the DCOG-LATER cohort

PURPOSE: Childhood cancer survivors are at increased risk of developing subsequent malignant neoplasms (SMNs). We compared survival and clinical characteristics of survivors with SMNs (sarcoma, breast cancer, or melanoma) and a population-based sample of similar first malignant neoplasm (FMN) patients.METHODS: We assembled three case series of solid SMNs observed in a cohort of 5-year Dutch childhood cancer survivors diagnosed 1963-2001 and followed until 2014: sarcoma (n = 45), female breast cancer (n = 41), and melanoma (n = 17). Each SMN patient was sex-, age-, and calendar year-matched to 10 FMN patients in the population-based Netherlands Cancer Registry. We compared clinical and histopathological characteristics by Fisher's exact tests and survival by multivariable Cox regression and competing risk regression analyses.RESULTS: Among sarcoma-SMN patients, overall survival [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.23-2.87] and sarcoma-specific mortality (HR 1.91, 95% CI 1.16-3.13) were significantly worse compared to sarcoma-FMN patients (foremost for soft-tissue sarcoma), with 15-year survival rates of 30.8% and 61.6%, respectively. Overall survival did not significantly differ for breast-SMN versus breast-FMN patients (HR 1.14, 95% CI 0.54-2.37), nor for melanoma-SMN versus melanoma-FMN patients (HR 0.71, 95% CI 0.10-5.00). No significant differences in tumor characteristics were observed between breast-SMN and breast-FMN patients. Breast-SMN patients were treated more often with mastectomy without radiotherapy/chemotherapy compared to breast-FMN patients (17.1% vs. 5.6%).CONCLUSIONS: Survival of sarcoma-SMN patients is worse than sarcoma-FMN patients. Although survival and tumor characteristics appear similar for breast-SMN and breast-FMN patients, treatment differs; breast-SMN patients less often receive breast-conserving therapy. Larger studies are necessary to substantiate these exploratory findings.</p

A detailed insight in the high risks of hospitalizations in long-term childhood cancer survivors-A Dutch LATER linkage study

Background Insight in hospitalizations in long-term childhood cancer survivors (CCS) is useful to understand the impact of long-term morbidity. We aimed to investigate hospitalization rates and underlying types of diagnoses in CCS compared to matched controls, and to investigate the determinants. Me

Long-Term Tubular Dysfunction in Childhood Cancer Survivors; DCCSS-LATER 2 Renal Study

Simple Summary We studied survivors of childhood cancer who received cancer treatment that might affect the kidneys and compared them to controls from the general population. We investigated if there was a difference in the occurrence of tubular dysfunction. The tubules are the part of the kidney responsible for reabsorption of needed substances to the blood and the removal of wastes. After around 25 years since their cancer diagnosis, we found that in general there were no differences between survivors and controls, but survivors more often had losses of small proteins in the urine. Yet, some survivors of childhood cancer were found to have an increased risk of tubular dysfunction. Namely, survivors treated with the chemotherapeutic agents ifosfamide, cisplatin or carboplatin. Therefore, these patients should be monitored during their follow-up. The aim of this nationwide cross-sectional cohort study was to determine the prevalence of and risk factors for tubular dysfunction in childhood cancer survivors (CCS). In the DCCSS-LATER 2 Renal study, 1024 CCS (>= 5 years after diagnosis), aged >= 18 years at study, treated between 1963 and 2001 with potentially nephrotoxic therapy (i.e., nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide, or hematopoietic stem cell transplantation) participated, and 500 age- and sex-matched participants from Lifelines acted as controls. Tubular electrolyte loss was defined as low serum levels (magnesium 1.7 mg/mmol was considered as low-molecular weight proteinuria (LMWP). Multivariable risk analyses were performed. After median 25.5 years follow-up, overall prevalence of electrolyte losses in CCS (magnesium 5.6%, potassium 4.5%, phosphate 5.5%) was not higher compared to controls. LMWP was more prevalent (CCS 20.1% versus controls 0.4%). LMWP and magnesium loss were associated with glomerular dysfunction. Ifosfamide was associated with potassium loss, phosphate loss (with cumulative dose > 42 g/m(2)) and LMWP. Cisplatin was associated with magnesium loss and a cumulative dose > 500 mg/m(2) with potassium and phosphate loss. Carboplatin cumulative dose > 2800 mg/m(2) was associated with potassium loss. In conclusion, long-term tubular dysfunction is infrequent. Yet, ifosfamide, cisplatin and carboplatin are risk factors

Crystal IS on the move

Introduction: Whether pediatric patients with differentiated thyroid carcinoma (DTC) are at risk of developing treatment-related adverse effects on cardiac function is unknown. We therefore studied in long-term survivors of pediatric DTC the prevalence of cardiac dysfunction and atrial fibrillation in relation to treatment variables, and the association between cardiac dysfunction and plasma biomarkers. Methods: In this nationwide prospective multicenter study, cardiac assessments were performed in 66 adult survivors of pediatric DTC (age at diagnosis 18 years and follow-up 5 years after diagnosis) treated in the Netherlands between 1970 and 2009. Assessment included echocardiography, plasma biomarkers (N-terminal pro-brain natriuretic peptide, high-sensitive troponin-T, galectin-3), and 24-hour Holter electrocardiography. Echocardiographic measurements were compared with retrospective data of 66 sex- and age-matched unaffected Dutch controls. Diastolic dysfunction was defined as an early diastolic septal and/or lateral tissue velocity (e) less than 2 SD of mean age-adjusted reference data. Results: The survivors (86.4% women) had at DTC diagnosis a median age of 16 years. Median follow-up was 17 years. Left ventricular ejection fraction <50% was found in one survivor, and median global longitudinal systolic strain was near normal. Diastolic dysfunction was present in 14 asymptomatic survivors (21.2%). Overall, diastolic function of survivors was lower compared with controls (emean 14.5 versus 15.8cm/s, P=0.006). Older attained age and higher waist circumference were associated with decreased diastolic function, whereas thyrotropin levels and cumulative administered radioiodine dose were not. In survivors, biomarkers were not associated with diastolic dysfunction; atrial fibrillation was not observed. Conclusion: While systolic function is unaffected, diastolic dysfunction is frequently observed in asymptomatic long-term survivors of pediatric DTC, which may suggest early cardiac agin