Impact of age on survival according to molecular tumor findings in children and adolescents with soft-tissue and bone sarcoma: The BIOSCA project.

BACKGROUND: Adolescents (15-19 years) with sarcoma are known to have significantly worse survival than children (0-14 years). One possible reason may be that the adolescent sarcomas exhibit specific biological characteristics resulting in differences in clinical presentation and treatment resistance behaviors. The BIOSCA project aims to further explore these age-related differences in survival accounting for molecular tumor characteristic in children and adolescents with sarcoma. METHODS: A retrospective national population-based observational study with documented somatic genetic analyses was conducted between 2011 and 2016 of all patients aged from 0 to 17 years with a diagnosis of sarcoma using the National Registry of Childhood Cancers Database. RESULTS: A total of 1637 children (0-9years: 40%), preadolescents (10-14years: 35%) and adolescents (15-17 years: 25%) with a diagnosis of bone (N = 845) or soft-tissue (N = 792) sarcoma were included. Adolescents had significantly worse outcome for undifferentiated small round cell sarcoma (USRCS), alveolar rhabdomyosarcoma (ARMS), and epithelioid sarcoma. Five-year overall survivals were worse among CIC-rearranged USRCS cases (47% [95%CI:21-69]) as compared to other USRCS, and PAX3::FOXO1 ARMS patients (44% [95%CI:32-55]) as compared to other ARMS. Adjusting for stage and genomic-profiling status, adolescents with USRCS were 1.6-fold more likely to die than children (P = 0.05), while the difference in survival between age of ARMS patients was weaken. Indeed, the prevalence of PAX3::FOXO1 increased significantly with age. CONCLUSION: Age was an independent prognostic factor of outcome only in patients with USRCS, while the association between age and survival of patients with ARMS could be partly explained by differences in prevalence of PAX3::FOXO1.

PAX-FOXO1 fusion status in children and adolescents with alveolar rhabdomyosarcoma: Impact on clinical, pathological, and survival features.

BACKGROUND: Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer and cases with fusion PAX3-FOXO1 and PAX7-FOXO1 seem to have a poor prognosis. The aim is to evaluate whether PAX-FOXO1 alterations influence clinical outcome in childhood and adolescence population with ARMS. PROCEDURE: A population-based study was conducted between 2011 and 2016 in patients less than 17 years with a diagnosis of ARMS. Overall survival (OS) depending on fusion status with clinical factors was analyzed. RESULTS: Out of 111 ARMS patients recorded in the French National Childhood Cancer Registry during the 2011-2016 period, 61% expressed PAX3-FOXO1, 15% expressed PAX7-FOXO1, 13% were FOXO1 fusion-positive without PAX specification, and 7% were PAX-FOXO1 negative (n = 4 missing data). Compared to patients with PAX7-FOXO1 positive ARMS, those with PAX3-FOXO1 positive tumor were significantly older (10-17 years: 57.4% vs. 29.4%), and had more often a metastatic disease (54.4% vs. 23.5%). Poorer 5-year OS for patients with PAX3-FOXO1 and PAX not specified FOXO1-positive tumor were observed (44.0% [32.0-55.4] and 35.7% [13.1-59.4], respectively). After adjustment for stage at diagnosis, patients with positive tumor for PAX3-FOXO1 were 3.6-fold more likely to die than those with positive tumor for PAX7-FOXO1. CONCLUSION: At the population level, PAX3-FOXO1 was associated with a significant higher risk of death compared to PAX7-FOXO1-positive and PAX-FOXO1-negative tumors, and could explain poorer 5-year OS observed in adolescence population diagnosed with ARMS. A continuous risk score derived from the combination of clinical parameters with PAX3-FOXO1 fusion status represents a robust approach to improving current risk-adapted therapy for ARMS.

Seasonality of main childhood embryonal tumours and rhabdomyosarcoma, France, 2000-2015.

Few studies have investigated the seasonal patterns of embryonal tumours. Based on data from the French National Registry of Childhood Cancers, the present study aimed to investigate seasonal variations in embryonal tumour incidence rates by month of birth and by month of diagnosis. The study included 6635 primary embryonal tumour cases diagnosed before the age of 15 years over the period 2000-2015 in mainland France. Assuming monthly variations in incidence rates were homogeneous over 2000-2015, we used a Poisson regression model to test for overall heterogeneity in standardised incidence ratios (SIRs) by month of birth or diagnosis. The seasonal scan statistic method was used to detect monthly excesses or deficits of embryonal tumour cases over the whole study period. The annual reproducibility of the observed monthly variations was formally tested. An overall heterogeneity in incidence rates by month of birth was observed for rhabdomyosarcoma in boys only. Based on the month of diagnosis, a seasonality was evidenced for unilateral retinoblastoma, with a lower incidence rate in the summer (SIRJul-Aug  = 0.68, 95% CI = 0.52-0.87), whilst the incidence rate of rhabdomyosarcoma tended to be lower in August (SIRAug  = 0.68, 95% CI = 0.52-0.89). No seasonality was detected for the other embryonal tumour groups by month of birth or month of diagnosis. This study is one of the largest to have investigated the seasonality of childhood embryonal tumours. The study showed a seasonal variation in the incidence rates by month of diagnosis for unilateral retinoblastoma and rhabdomyosarcoma. Our findings are likely to reflect a delay in consultation during the summer months. However, the role of seasonally varying environmental exposures cannot be ruled out.

Thyroid cancers in children and adolescents in France: Incidence, survival and clinical management over the 2000-2018 period.

INTRODUCTION: Thyroid cancer is the first cause of endocrine malignancy among children. Over the past decades, an increase in the incidence rates (IR) has been observed around the world. Our study aimed to describe epidemiology, therapeutic management and survival rates of children and adolescents with thyroid cancer in France. METHODS: A population-based study was conducted between 2000 and 2018 in children and adolescents less than 17 years with a diagnostic of thyroid cancer. RESULTS: A total of 774 thyroid cancers were included: 579 papillary (PTC), 83 follicular (FTC), and 111 medullary carcinomas (MTC). PTC are more frequent in females and in adolescents whereas MTC mainly concerned children, mostly with a familial predisposition. Almost all patients underwent thyroidectomy, completed for most patients with PTC and FTC by radioiodine therapy. Cervical dissection was performed more frequently in patients having PTC and MTC compared to those with FTC. Between 2000 and 2018, thyroid cancers IR in children fluctuated between 1.3 and 3.2 per million, without any significant trend. The median follow-up time was 11.3 years in children, and 5.7 years in adolescents. The 5year-OS was greater than 98.5%. CONCLUSIONS: Population-based studies are crucial for better understanding and delineation of best management of rare diseases as thyroid cancers in pediatric and adolescent population. Considering the very favorable survival, a stratification should be proposed between cases at low risk and cases at high risk of relapse, in order to consider a strategy of therapeutic de-escalation in the most favorable cases.

Childhood head and neck cancer in France: Incidence, survival and trends from 2000 to 2015.

INTRODUCTION: Childhood head and neck cancers (HNC) are rare and represent a complex group of anatomical topographies. The aim of this study is to describe the distribution, the incidence and survival rates of children with malignant HNC in France. METHODS: A population-based study was conducted between 2000 and 2015 in children less than 15 years with a diagnosis of HNC using the French National Registry of Childhood Cancers database (RNCE). Age-standardized incidence rates (ASR) and survival analysis were performed. RESULTS: The 1623 included HNC represented 5.6% of all cancers included in the RNCE. The thyroid was the leading tumor site category (26.6%), followed by head and neck soft tissue location (15.4%) and the nasopharynx (10.8%). The most common cancers were thyroid gland carcinomas (26.1%), rhabdomyosarcomas (23.9%) and Burkitt Lymphomas (8.6%). Nasopharynx cancers and soft-tissue sarcomas were statistically more frequent in boys, while thyroid carcinomas were significantly more frequent in girls. The annual ASR was 8.6 new cancer cases per million children. For all HNC combined, the 5-year overall survival (OS) was 87.7% [95%CI: 85.9-89.2]. There was no statistically significant variation in 5-year OS between 2000-2007 and 2008-2015. CONCLUSIONS: Epidemiological data on HNC distribution, incidence and survival contributes to better understand these tumors by quantifying their impact on the French population and assessing their burden. Regarding the exclusion of topographies and some histological origins performed by some authors, this report proposes new recommendations to study HNC in a pediatric population.

Factors associated with 5- and 10-year survival among a recent cohort of childhood cancer survivors (France, 2000-2015).

BACKGROUND: Childhood cancer survival currently exceeds 80 % five years after diagnosis in high-income countries. In this study, we aimed to describe long-term trends and to investigate socioeconomic and spatial disparities in childhood cancer survival. METHODS: The study included 28,073 cases recorded in the French National Registry of Childhood Cancers from 2000 to 2015. Contextual census data (deprivation indices, population density, spatial accessibility to general practitioners) were allocated to each case based on the residence at diagnosis. Overall survival (OS) and conditional 10-year OS for 5-year survivors were estimated for all cancers combined and by diagnostic group and subgroup. Comparisons were conducted by sex, age at diagnosis, period of diagnosis, and contextual indicators. Hazard ratios for death were estimated using Cox models. RESULTS: All cancers combined, the OS reached 82.8 % [95 % CI: 82.4-83.3] at 5 years and 80.8 % [95 % CI: 80.3-81.3] at 10 years. Conditional 10-year OS of 5-year survivors reached 97.5 % [95 % CI: 97.3-97.7] and was higher than 95 % for all subgroups except osteosarcomas and most subgroups of the central nervous system. In addition to disparities by sex, age at diagnosis, and period of diagnosis, we observed a slight decrease in survival for cases living in the most deprived areas at diagnosis, not consistent across diagnostic groups. CONCLUSION: Our results confirm the high 5-year survival for childhood cancer and show an excellent 10-year conditional survival of 5-year survivors. Additional individual data are needed to clarify the factors underlying the slight decrease in childhood cancer survival observed in the most deprived areas.

Infant cancers in France: Incidence and survival (2000-2014).

BACKGROUND: On average 185 children are diagnosed each year in France with a cancer in their first year of life, representing 11 % of cancers diagnosed in children less than 15 years. METHODS: A retrospective population-based observational study was conducted between 2000 and 2014 of all infants with a diagnosis of cancer using the National Registry of Childhood Cancers Database. RESULTS: Out of 2760 cases of primary cancers in infancy, there were mainly neuroblastomas 30.1 %), central nervous system (CNS) tumors (16.1 %), leukemias (15.3 %), retinoblastomas (11.6 %), and Wilms tumors (6.9 %). Embryonal malignancies accounted for 55.2 % of cases. Most diagnoses showed a male excess, particularly for malignant gonadal germ-cell tumors (GCT) with a 17.5 sex-ratio. The annual incidence rate, 242.9 per million infants overall, was stable over the study period for all types of cancer. Most deaths occurred within the first month of life (70.8 % of deaths). The 5-year overall survival (5-y OS) was 81.0 % (95 %CI, 79.4-82.4) with large contrasts between diagnoses. The best 5-y OS (>85 %) were observed for retinoblastomas, carcinomas, nephroblastomas, GCT, neuroblastomas, and hepatoblastomas. Conversely, the lowest 5-y OS (<65 %) were observed for acute myeloid leukemias, CNS tumors, and lymphoid leukemias. We observed no substantial change over time (80.5 % [95 %CI, 77.7-82.9] in 2000-2004 and 82.6 % [95 %CI, 80.0-84.9] in 2010-2014) for all cancers combined. The same result has been found whatever the diagnostic group. CONCLUSION: Our results contribute to better understand these tumors by quantifying their impact on the French population and assessing the burden of some devastating infant cancers.

Ecological association between residential natural background radiation exposure and the incidence rate of childhood central nervous system tumors in France, 2000-2012.

BACKGROUND: High-dose ionizing radiation is an established risk factor for childhood central nervous system tumors (CNST) but the role of low doses remains debated. In particular, there are few studies of natural background radiation (NBR, gamma radiation and radon) and childhood CNST, and their results are inconclusive. OBJECTIVES: This study aimed to investigate the ecological association between NBR exposure and childhood CNST incidence in France, considering childhood CNST overall and by subgroups. METHODS: Incidence data were provided by the French national registry of childhood cancers, which has high completeness. We included 5471 childhood CNST cases registered over the period 2000-2012, and their municipality of residence at diagnosis was recorded. Municipality NBR exposures were estimated by cokriging models, using NBR measurements and additional geographic data. The incidence rate ratio (IRR) per unit variation of exposure was estimated with Poisson regression models. NBR exposures were considered at the time of diagnosis, and cumulatively from birth to diagnosis. In an exploratory analysis, the total brain dose due to NBR was used. RESULTS: Overall, there was no association between NBR exposure and childhood CNST incidence (IRR = 1.03 (0.98,1.09) per 50 nSv/h for gamma radiation, and IRR = 1.02 (0,96,1.07) per 100 Bq/m3 for radon). An association was suggested between pilocytic astrocytomas and gamma radiation (IRR = 1.12 (1.00,1.24) per 50 nSv/h) but not with radon (IRR = 1.07 (0.95,1.20) per 100 Bq/m3). Upward trends for this CNST subtype were also suggested with the cumulative exposures to gamma radiation and the total brain dose. NBR exposure was not associated with other CNST subgroups (ependymomas, embryonal tumors, and gliomas other than pilocytic astrocytomas). Adjustment for socio-demographic factors did not change the findings. CONCLUSIONS: Our study was based on high quality incidence data, large numbers of CNST cases, and validated models of NBR exposure assessment. Results suggest an association between gamma radiation, as a component of NBR, and pilocytic astrocytomas incidence in France.

Spatial and temporal variations of childhood cancers: Literature review and contribution of the French national registry.

BACKGROUND: Significant increases in childhood cancer incidence since the 1970s have been consistently reported worldwide, but the persistence of the increase on recent periods is discussed. No conclusion can be drawn concerning the spatial variations of childhood cancer, either. This study is an in-depth investigation of the spatial and temporal variations of childhood cancer in France. An extensive review of all the studies published since 2000 on those issues is provided. METHODS: The study included 25 877 cases of childhood cancer registered nationwide over 2000-2014. The spatial heterogeneity (overdispersion, autocorrelation, overall heterogeneity) was tested, on two geographic scales, and two spatial scan methods were used to detect clusters of cases. The annual average percent change (AAPC) in incidence rate was estimated with Poisson regression models, and joinpoint analyses were considered. RESULTS: Glioma and non-Hodgkin lymphoma cases exhibited some spatial heterogeneity and two large clusters were detected. Overall, the incidence rate of childhood cancer was stable over 2000-2014 (AAPC = -0.1% [-0.3%; 0.2%]). A log-linear positive trend was significantly evidenced for gliomas other than pilocytic astrocytomas (AAPC = 1.8% [0.9%; 2.7%]), with some suggestion of a leveling-off at the end of the period, while Burkitt lymphoma and germ cell tumor incidence rates decreased (AAPC = -2.2% [-3.8%; -0.5%] and AAPC = -1.9% [-3.4%; -0.3%], respectively). No spatial heterogeneity or significant time variation was evidenced for other cancers. CONCLUSION: Several types of childhood cancer displayed some spatial heterogeneity and two large clusters were detected, the origins of which are to be investigated and might include differences in case ascertainment. Overall, the results do not support a sustained increase in incidence rates of childhood cancer in recent years.

Risk of Childhood Cancer and Socio-economic Disparities: Results of the French Nationwide Study Geocap 2002-2010.

BACKGROUND: Socio-economic status is related to many life style and environmental factors, some of which have been suggested to influence the risk of childhood cancer. Studies requiring subject participation are usually hampered by selection of more educated parents. To prevent such bias, we used unselected nationwide Geographical Information System (GIS)-based registry data, to investigate the influence of socio-economic disparities on the risk of childhood cancer. METHODS: The Geocap study included all French residents diagnosed with cancer aged up to 15 years over the period 2002-2010 (15 111 cases) and 45 000 contemporaneous controls representative of the childhood population. Area socio-economic characteristics used to calculate the European Deprivation Index (EDI) were based on census data collected on the fine scale of the Merged Islet for Statistical Information (IRIS). RESULTS: Overall, the risk of acute lymphoblastic leukaemia (ALL) was lower in the most deprived quintile than in the other quintiles of EDI (ORQ5vs

Neonatal Solid Tumors: Incidence and Survival in France.

BACKGROUND: Solid tumors are uncommon in the neonatal period but represent an important cause of mortality and morbidity. PROCEDURE: Using the French National Registry of Childhood Solid Tumors database, all children, from birth to 28 days of age inclusive, with a primary malignant solid tumor diagnosed between 2000 and 2009 in mainland France were identified. Tumors were classified according to the third version of the International Classification of Childhood Cancer. RESULTS: Of total 285 solid tumors over 10 years, the most common cancer was neuroblastoma (47%), followed by germ cell tumors (29%), central nervous system tumors (10%), and soft tissue sarcomas (8%). The annual incidence was 36.6 per million live births. No statistically significant change in time trends of incidence was observed during 2000-2009. Routine ultrasonography during pregnancy established the diagnosis in 52% of cases. Thirteen neonates (4.5%) had congenital abnormalities associated with their tumors. For all solid tumors combined, overall survival was 84.2% (95% CI, 79.4-87.9) at 1 year and 83.8% (95% CI, 79.0-87.6) at 5 years. More favorable prognosis was significantly associated with neonates treated by surgery (65% of cases) compared to those without tumor excision. However, perioperative and postoperative mortality was 8%. CONCLUSIONS: Because of their relative rarity, there is a paucity of objective information on the epidemiology, optimal treatment, and long-term outcome of neonatal solid tumors. But to obtain a clearer picture of the epidemiology of neonatal tumors, it is essential to have some recommendations on the methodological approach used to study them.

Childhood cancer survival in France, 2000-2008.

This paper reports the latest survival data for French childhood cancer patients at the national level. Data from the two French National Registries of Childhood Cancer (Haematopoietic Malignancies and Solid Tumours) were used to describe survival outcomes for 15,479 children diagnosed with cancer between 2000 and 2008 in mainland France. The overall survival was 91.7% at 1 year, 86.9% at 2 years and 81.6% at 5 years. Relative survival did not differ from overall survival even for infants. Survival was lower among infants for lymphoblastic leukaemia and astrocytoma, but higher for neuroblastoma. For all cancers considered together, 5-year survival increased from 79.5% in the first (2000-2002) diagnostic period to 83.2% in the last (2006-2008) period. The improvement was significant for leukaemia, both myeloid and lymphoid, central nervous system tumours (ependymoma) and neuroblastoma. The results remained valid in the multivariate analysis, and, for all cancers combined, the risk of death decreased by 20% between 2000-2002 and 2006-2008. The figures are consistent with various international estimates and are the result of progress in treatment regimens and collaborative clinical trials. The challenge for the French registries is now to study the long-term follow-up of survivors to estimate the incidence of long-term morbidities and adverse effects of treatments.

Incidence and survival of children with central nervous system primitive tumors in the French National Registry of Childhood Solid Tumors.

BACKGROUND: Central nervous system (CNS) tumors are the second most common childhood malignancy. The French National Registry of Childhood Solid Tumors (NRCST) makes it possible to describe this variety of distinct tumor types and to provide incidence and survival data in France on a nationwide basis. METHODS: All children aged 0-14 years, who were registered with a primary CNS tumor in the NRCST of France between 2000 and 2008, were identified. Tumors were classified according to the International Classification of Childhood Cancer, third edition. RESULTS: Approximately 57% of pediatric CNS tumors were gliomas, with astrocytomas of the pilocytic type predominating. Distributions of subtypes by age showed that primitive neuroectodermal tumors and ependymomas mainly occurred in children aged <5 years. The mean annual incidence rate of CNS tumors was 39 per million. No statistically significant change in time trends of incidence rate was observed during 2000-2008. For all tumors combined, overall survival was 84.8% (95% CI, 83.7%-85.9%) at 1 year and 72.9% (95% CI, 71.5%-74.3%) at 5 years. Survival time trends were studied in a multivariate analysis observing a reduction in the risk of death in periods of diagnosis 2003-2005 (HR = 0.8; 95% CI, 0.7­0.9) and 2006-2008 (HR = 0.7; 95% CI, 0.6-0.9) compared with 2000-2002. CONCLUSIONS: The stable incidence rates during the last 10 years could indicate that major changes in environmental risk factors are unlikely, but the ongoing need for population-based surveillance remains relevant. Results indicate a positive trend in the survival probability still persistent in the 2000s.

Incidence of childhood cancer in France: National Children Cancer Registries, 2000-2004.

The French National Registry of Childhood Haematopoietic Malignancies and the French National Registry of Childhood Solid Tumours jointly ensure the surveillance of cancer in children aged less than 15 years in mainland France. During the period 2000-2004, the registries recorded a total of 8473 cases: 3446 cases of haematological malignancies and 5027 cases of solid tumours. The average number of sources per case was 2.7 and diagnosis was documented by cytology/histology in 94% of cases, ensuring high quality data. The age-standardized incidence rate for all cancers combined was 156.6 cases per million children per year, with a sex ratio of 1.2. The most frequent cancers were leukaemia (29%), central nervous system tumour (23%), lymphoma (12%) and neuroblastoma (8%). In France, an estimated one out of every 440 children presents with cancer before the age of 15 years. The incidence rates are close to those of other industrialized countries, but somewhat higher than those estimated by the French local registries for the period 1990-1999, probably because of improved methodology or perhaps a real increase in some rates. The French National Registries of Childhood Cancer have shown that they are able to fulfil public health surveillance missions satisfactorily and support the national programme for research on childhood cancer.