Genetic risk of second malignant neoplasm after childhood cancer treatment: A systematic review.

Second malignant neoplasm (SMN) is one of the most severe long-term risks for childhood cancer survivors (CCS), significantly impacting long-term patient survival. While radiotherapy and chemotherapy are known risk factors, the observed inter-individual variability suggests a genetic component contributing to the risk of SMN. This article aims to conduct a systematic review of genetic factors implicated in the SMN risk among CCS. Searches were performed in PubMed, Scopus, and Web of Sciences. Eighteen studies were included (eleven candidate gene studies, three genome-wide association studies, and four whole exome/genome sequencing studies). The included studies were based on different types of first cancers, investigated any or specific types of SMN, and focused mainly on genes involved in drug metabolism and DNA repair pathways. These differences in study design and methods used to characterize genetic variants limit the scope of the results and highlight the need for further extensive and standardized investigations. However, this review provides a valuable compilation of SMN risk-associated variants and genes, facilitating efficient replication and advancing our understanding of the genetic basis for this major risk for CCS.

Radiation doses received by major organs at risk in children and young adolescents treated for cancer with external beam radiation therapy: a large-scale study from 12 European countries.

BACKGROUND: Childhood cancer survivors are at high risk of long-term iatrogenic events, in particular those treated with radiotherapy. The prediction of risk of such events is mainly based on the knowledge of the radiation dose received to healthy organs and tissues during treatment of childhood cancer diagnosed decades ago. PURPOSE: We aimed to set up a standardised organ dose table in order to help former patients and clinician in charge of long term follow-up clinics. MATERIAL AND METHODS: We performed whole body dosimetric reconstruction for 2646 patients from 12 European Countries treated between 1941 and 2006 (median: 1976). Most planning were 2D or 3D, 46% of patients were treated using Cobalt 60 and 41% using linear accelerator, the median prescribed dose being 27.2 Gy (IQ1-IQ3: 17.6-40.0 Gy), A patient specific voxel-based anthropomorphic phantom with more than 200 anatomical structures or sub-structures delineated as a surrogate of each subject's anatomy was used. The radiation therapy was simulated with a treatment planning system (TPS) based on available treatment information. The radiation dose received by any organ of the body was estimated by extending the TPS dose calculation to the whole-body, by type and localisation of childhood cancer. RESULTS: The integral dose and normal-tissue doses to most of the 23 considered organs increased between the 1950's and the 1970's and decreased or plateaued thereafter. Whatever the organ considered, the type of childhood cancer explained most of the variability in organ dose. The country of treatment explained only a small part of the variability. CONCLUSION: The detailed dose estimates provide very useful information for former patients or clinicians who have only limited knowledge about radiation therapy protocols or techniques, but who know the type and site of childhood cancer, gender, age and year of treatment. This will allow better prediction of the long-term risk of iatrogenic events and better referral to long-term follow-up clinics.

Risk of subsequent gliomas and meningiomas among 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.

BACKGROUND: Childhood cancer survivors are at risk of subsequent gliomas and meningiomas, but the risks beyond age 40 years are uncertain. We quantified these risks in the largest ever cohort. METHODS: Using data from 69,460 5-year childhood cancer survivors (diagnosed 1940-2008), across Europe, standardized incidence ratios (SIRs) and cumulative incidence were calculated. RESULTS: In total, 279 glioma and 761 meningioma were identified. CNS tumour (SIR: 16.2, 95% CI: 13.7, 19.2) and leukaemia (SIR: 11.2, 95% CI: 8.8, 14.2) survivors were at greatest risk of glioma. The SIR for CNS tumour survivors was still 4.3-fold after age 50 (95% CI: 1.9, 9.6), and for leukaemia survivors still 10.2-fold after age 40 (95% CI: 4.9, 21.4). Following cranial radiotherapy (CRT), the cumulative incidence of a glioma in CNS tumour survivors was 2.7%, 3.7% and 5.0% by ages 40, 50 and 60, respectively, whilst for leukaemia this was 1.2% and 1.7% by ages 40 and 50. The cumulative incidence of a meningioma after CRT in CNS tumour survivors doubled from 5.9% to 12.5% between ages 40 and 60, and in leukaemia survivors increased from 5.8% to 10.2% between ages 40 and 50. DISCUSSION: Clinicians following up survivors should be aware that the substantial risks of meningioma and glioma following CRT are sustained beyond age 40 and be vigilant for symptoms.

Surveillance after childhood cancer: are survivors with an increased risk for cardiomyopathy regularly followed-up?

BACKGROUND: We aimed to study adherence to cardiac screening in long-term childhood cancer survivors (CCS) at high risk of cardiomyopathy. METHODS: This study involved 976 5-year CCS at high risk for cardiomyopathy from the French Childhood Cancer Survivor Study. Determinants of adherence to recommended surveillance were studied using multivariable logistic regression models. Association of attendance to a long-term follow-up (LTFU) visit with completion of an echocardiogram was estimated using a Cox regression model. RESULTS: Among participants, 32% had an echocardiogram within the 5 previous years. Males (adjusted RR [aRR] 0.71, 95% CI 0.58-0.86), survivors aged 36-49 (aRR 0.79, 95% CI 0.64-0.98), Neuroblastoma (aRR 0.53, 95% CI 0.30-0.91) and CNS tumour survivors (aRR 0.43, 95% CI 0.21-0.89) were less likely to adhere to recommended surveillance. Attendance to an LTFU visit was associated with completion of an echocardiogram in patients who were not previously adherent to recommendations (HR 8.20, 95% CI 5.64-11.93). CONCLUSIONS: The majority of long-term survivors at high risk of cardiomyopathy did not adhere to the recommended surveillance. Attendance to an LTFU visit greatly enhanced the completion of echocardiograms, but further interventions need to be developed to reach more survivors.

Predictive factors of long-term follow-up attendance in very long-term childhood cancer survivors.

BACKGROUND: Long-term follow-up (LTFU) clinics have been developed but only some childhood cancer survivors (CCS) attend long-term follow-up (LTFU). OBJECTIVE: To identify factors that influence LTFU attendance. METHODS: Five-year CCS treated for a solid tumor or lymphoma in Gustave Roussy before 2000, included in the FCCSS cohort (French Childhood Cancer Survivor Study), aged >18 years and alive at the date of the LTFU Clinic opening (January 2012) were invited to a LTFU visit. Factors associated with attendance at the LTFU clinic between 2012 and 2020 were estimated using logistic regression analyses. Analyses included different types of factors: clinical (tumor characteristics, cancer treatments, late effects), medical (medical expenses were used as a proxy of survivor's health status), social (deprivation index based on census-tract data relating to income, educational level, proportion of blue-collar workers, and unemployed people living in the area of residence), and spatial (distance to the LTFU clinic). RESULTS: Among 2341 CCS contacted (55% males, mean age at study, 45 years; SD ± 10 years; mean age at diagnosis, 6 years; SD ± 5 years), 779 (33%) attended at least one LTFU visit. Initial cancer-related factors associated with LTFU visit attendance were: treatment with both radiotherapy and chemotherapy (odds ratio [OR], 4.02; 95% CI, 2.11-7.70), bone sarcoma (OR, 2.43; 95% CI, 1.56-3.78), central nervous system primitive tumor (OR, 1.65; 95% CI, 1.02-2.67), and autologous hematopoietic cell transplant (OR, 2.07; 95% CI, 1.34-3.20). Late effects (OR, 1.70; 95% CI, 1.31-2.20), highest medical expenses (OR, 1.65; 95% CI, 1.22-2.22), living in the most advantaged area (OR vs. the most deprived area = 1.60; 95% CI, 1.15-2.22), and shorter distance from LTFU care center (<12 miles) also increased attendance. CONCLUSIONS: Patients who are apparently healthy as well as socially disadvantaged and living far away from the center are less likely to attend LTFU care. PLAIN LANGUAGE SUMMARY: Among 2341 adult childhood cancer survivors contacted between 2012 and 2020, 33% attended at least one long-term follow-up visit. Clinical factors related to attendance were multimodal treatment of first cancer (combining chemotherapy and radiotherapy), stem cell transplant, type of diagnosis (bone tumor and central nervous system primitive tumor), late effects (at least one disease among second malignancy, heart disease, or stroke), and highest medical expenses. In addition, the study identified social and spatial inequalities related to attendance, with independent negative effects of distance and social deprivation on attendance, even though the medical costs related to the long-term follow-up examinations are covered by the French social security system.

Risk factors for obesity in adulthood among survivors of childhood cancer.

OBJECTIVE: The aim of this study was to identify risk factors for obesity in childhood cancer survivors (CCSs). METHODS: The study included 3199 patients of the French Childhood Cancer Survivor Study cohort, with 303 patients with obesity who had returned the self-questionnaire. Analyses were adjusted for social deprivation index and sex. RESULTS: CCSs were less likely to have obesity (9.5%; 95% CI: 8.5%-10.5%) than expected from the general French population rates (12.5%; p = 0.0001). Nevertheless, brain tumor survivors were significantly more likely to develop obesity than the general French population (p = 0.0001). Compared with patients who did not receive radiotherapy to the pituitary gland, those who received a dose >5 Gy had an increased risk of obesity: relative risk 1.9 (95% CI: 1.2-3.1), 2.5 (95% CI: 1.7-3.7), and 2.6 (95% CI: 1.6-4.3), respectively, for participants with 6 to 20 Gy, 20 to 40 Gy, and ≥40 Gy of radiation. Etoposide administration significantly increased the risk of obesity (relative risk 1.7; 95% CI: 1.1-2.6). High social deprivation index was also a risk factor, just like BMI at diagnosis. CONCLUSIONS: Long-term follow-up of CCSs should include weight follow-up during adulthood.

Locoregional treatment of primary tumor in synchronous metastatic head and neck squamous cell carcinomas.

PURPOSE: Patients with synchronous metastatic head and neck squamous cell carcinomas (mHNSCC) are at risk of locoregional progression associated with significant morbidity and mortality. The aim of this study is to assess whether the addition of aggressive locoregional treatment to systemic therapy could be associated with an improved overall survival (OS) compared to systemic therapy alone in upfront mHNSCC patients. MATERIAL AND METHODS: This retrospective study included patients presenting with previously untreated mHNSCC who underwent first-line systemic therapy at a single institution between 1998 and 2018. Locoregional treatment was defined as either exclusive locoregional radiotherapy (RT) or surgery with or without adjuvant RT. RESULTS: One hundred forty-eight patients were included. Eighty patients were treated with systemic therapy alone and 68 patients were treated with a combination of locoregional treatment and systemic therapy. Median overall survival (OS) was 13 months [10.7-15] and median progression free survival (PFS) was 7.7 month [6.5-8.9]. The addition of a locoregional treatment to systemic therapy compared to systemic therapy alone was associated with improved survival (1-year OS, 65.8% vs. 41.1%, p < .001, and 1-year PFS, 42.5% vs. 18.5%, p < .001). Moreover, RT dose equal to 70 Gy was associated with even longer OS compared to a RT dose below 70 Gy and to no locoregional treatment (23.4 vs. 12.7 vs 7.5 months respectively). In a subgroup analysis on 75 patients presenting with a responding or stable metastatic disease after first-line systemic therapy, oropharyngeal primary tumor site and the addition of a locoregional treatment, especially a high radiation dose of 70 Gy, were evidenced as independent prognostic factors for improved OS. CONCLUSION: The addition of a high-dose RT locoregional treatment to systemic therapy is associated with prolonged OS in patients with synchronous mHNSCC and should be discussed for patients who respond to or have a stable disease after first-line systemic therapy.

Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study.

PURPOSE: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

A Longitudinal Study of Individual Radiation Responses in Pediatric Patients Treated with Proton and Photon Radiotherapy, and Interventional Cardiology: Rationale and Research Protocol of the HARMONIC Project.

The Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy (photon and proton) in Pediatrics (HARMONIC) is a five-year project funded by the European Commission that aimed to improve the understanding of the long-term ionizing radiation (IR) risks for pediatric patients. In this paper, we provide a detailed overview of the rationale, design, and methods for the biological aspect of the project with objectives to provide a mechanistic understanding of the molecular pathways involved in the IR response and to identify potential predictive biomarkers of individual response involved in long-term health risks. Biological samples will be collected at three time points: before the first exposure, at the end of the exposure, and one year after the exposure. The average whole-body dose, the dose to the target organ, and the dose to some important out-of-field organs will be estimated. State-of-the-art analytical methods will be used to assess the levels of a set of known biomarkers and also explore high-resolution approaches of proteomics and miRNA transcriptomes to provide an integrated assessment. By using bioinformatics and systems biology, biological pathways and novel pathways involved in the response to IR exposure will be deciphered.

Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020.

Risk of Renal or Urinary Related Hospitalization in Survivors of Childhood Cancer: Results from the French Childhood Cancer Survivor Study.

BACKGROUND: Hospitalization rates can be used as an indirect indicator of the burden and severity of adverse health outcomes in childhood cancer survivors (CCS). We aimed to determine the long-term risks of hospitalization related to renal and urinary diseases among 5-year CCS. METHODS: The French Childhood Cancer Survivor Study cohort was linked with data from the French National Healthcare System database, which enabled the identification of hospitalizations related to renal or urinary diseases. Clinical and detailed treatment data were collected from medical records. Dose-volume histograms were estimated for all patients treated with radiotherapy. Standardized Hospitalization Ratios and absolute excess risks (AER) were calculated. Relative risks were estimated using Poisson regression. RESULTS: A total of 5,498 survivors were followed for 42,118 person-years (PY). Survivors experience 2.9 times more renal hospitalizations than expected in the general population, with an AER of 21.2/10,000 PY. Exposing more than 10% of the kidneys' volume to at least 20 Gray increases the risk of being hospitalized for renal causes by 2.2 (95% confidence interval, 1.3-3.6). Nephrectomized survivors treated with high doses of ifosfamide (>60 g/m²) have an extremely high risk of hospitalization for renal causes. Patients with comorbidities have about a 3-fold higher risk, and nephrectomized patients a 2-fold higher risk of being hospitalized for renal causes compared with other subjects. In the case of hospitalization for urinary causes, treatment by anthracycline administration was found to be associated with an almost 2-fold higher risk of hospitalization compared with the general population. CONCLUSIONS: These results support the need for careful monitoring of long-term renal diseases in survivors who have undergone nephrectomy, those treated with high doses of radiation (≥20 Gy) even to small volumes of the kidneys, and those with predisposing risk factors. IMPACT: This study provides new evidence with potential impact on surveillance guidelines related to dose-volume indicators associated with renal toxicity.

The risk of valvular heart disease in the French Childhood Cancer Survivors' Study: Contribution of dose-volume histogram parameters.

BACKGROUND AND PURPOSE: Valvular Heart Disease (VHD) is a known complication of childhood cancer after radiotherapy treatment. However, the dose-volume-effect relationships have not been fully explored. MATERIALS AND METHODS: We obtained individual heart Dose Volume Histograms (DVH) for survivors of the French Childhood Cancer Survivors Study (FCCSS) who had received radiotherapy. We calculated the Mean Dose to the Heart (MHD) in Gy, as well as the heart DVH parameters (Vd Gy, which represents the percentage of heart volume receiving at least d Gy), fixing the thresholds to 0.1 Gy, 5 Gy, 20 Gy, and 40 Gy. We analyzed them furtherly in the subpopulation of the cohort that was treated with a dose lower than 5 Gy (V0.1Gy|V5Gy=0%), 20 Gy (V5Gy|V20Gy=0%), and 40 Gy (V20Gy|V40Gy=0%), respectively. We investigated their role in the occurrence of a VHD in this population-based observational cohort study using the Cox proportional hazard model, adjusting for age at cancer diagnosis and chemotherapy exposure. RESULTS: Median follow-up was 30.6 years. Eighty-one patients out of the 7462 (1 %) with complete data experienced a severe VHD (grade ≥ 3). The risk of VHD increased along with the MHD, and it was associated with high doses to the heart (V40Gy < 50 %, hazard ratio (HR) = 7.96, 95 % CI: 4.26-14.88 and V20Gy|V40Gy=0% >50 %, HR = 5.03, 95 % CI: [2.35-10.76]). Doses 5-20 Gy to more than 50 % (V5Gy|V20Gy=0% >50 %) of the heart induced a marginally non-significant estimated risk. We also observed a remarkable risk increase with attained age. CONCLUSIONS: Our results provide new insight into the VHD risk that may impact current treatments and long-term follow-up of childhood cancer survivors.

Risk of subsequent primary oral cancer in a cohort of 69,460 5-year survivors of childhood and adolescent cancer in Europe: the PanCareSurFup study.

BACKGROUND: Survivors of childhood cancer are at risk of subsequent primary malignant neoplasms (SPNs), but the risk for rarer types of SPNs, such as oral cancer, is uncertain. Previous studies included few oral SPNs, hence large-scale cohorts are required to identify groups at risks. METHODS: The PanCareSurFup cohort includes 69,460 5-year survivors of childhood cancer across Europe. Risks of oral SPNs were defined by standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence. RESULTS: One hundred and forty-five oral SPNs (64 salivary gland, 38 tongue, 20 pharynx, 2 lip, and 21 other) were ascertained among 143 survivors. Survivors were at 5-fold risk of an oral SPN (95% CI: 4.4-5.6). Survivors of leukaemia were at greatest risk (SIR = 19.2; 95% CI: 14.6-25.2) followed by bone sarcoma (SIR = 6.4, 95% CI: 3.7-11.0), Hodgkin lymphoma (SIR = 6.2, 95% CI: 3.9-9.9) and soft-tissue sarcoma (SIR = 5.0, 95% CI: 3.0-8.5). Survivors treated with radiotherapy were at 33-fold risk of salivary gland SPNs (95% CI: 25.3-44.5), particularly Hodgkin lymphoma (SIR = 66.2, 95% CI: 43.6-100.5) and leukaemia (SIR = 50.5, 95% CI: 36.1-70.7) survivors. Survivors treated with chemotherapy had a substantially increased risk of a tongue SPN (SIR = 15.9, 95% CI: 10.6-23.7). CONCLUSIONS: Previous radiotherapy increases the risk of salivary gland SPNs considerably, while chemotherapy increases the risk of tongue SPNs substantially. Awareness of these risks among both health-care professionals and survivors could play a crucial role in detecting oral SPNs early.

Risk of subsequent primary lymphoma in a cohort of 69,460 five-year survivors of childhood and adolescent cancer in Europe: The PanCareSurFup study.

BACKGROUND: Survivors of Hodgkin lymphoma (HL) are at risk of developing non-Hodgkin lymphoma (NHL) after treatment; however, the risks of developing subsequent primary lymphomas (SPLs), including HL and NHL, after different types of childhood cancer are unknown. The authors quantified the risk of SPLs using the largest cohort of childhood cancer survivors worldwide. METHODS: The Pan-European Network for Care of Survivors After Childhood and Adolescent Cancer (PanCare) Survivor Care and Follow-Up Studies (PanCareSurFup) cohort includes 69,460 five-year survivors of childhood cancer, diagnosed during 1940 through 2008, from 12 European countries. Risks of SPLs were quantified by standardized incidence ratios (SIRs) and relative risks (RRs) using multivariable Poisson regression. RESULTS: Overall, 140 SPLs, including 104 NHLs and 36 HLs, were identified. Survivors were at 60% increased risk of an SPL compared with the general population (SIR, 1.6; 95% confidence interval [CI], 1.4-1.9). Survivors were twice as likely to develop NHL (SIR, 2.3; 95% CI, 1.9-2.8), with the greatest risks among survivors of HL (SIR, 7.1; 95% CI, 5.1-10.0), Wilms tumor (SIR, 3.1; 95% CI, 1.7-5.7), leukemia (SIR, 2.8; 95% CI, 1.8-4.4), and bone sarcoma (SIR, 2.7; 95% CI, 1.4-5.4). Treatment with chemotherapy for any cancer doubled the RR of NHL (RR, 2.1; 95% CI, 1.2-3.9), but treatment with radiotherapy did not (RR, 1.2; 95% CI, 0.7-2.0). Survivors were at similar risk of developing a subsequent HL as the general population (SIR, 1.1; 95% CI, 0.8-1.5). CONCLUSIONS: In addition to HL, the authors show here for the first time that survivors of Wilms tumor, leukemia, and bone sarcoma are at risk of NHL. Survivors and health care professionals should be aware of the risk of NHL in these survivors and in any survivors treated with chemotherapy.

Risk Factors for Heart Failure Among Pan-European Childhood Cancer Survivors: A PanCareSurFup and ProCardio Cohort and Nested Case-Control Study.

PURPOSE: Heart failure (HF) is a potentially life-threatening complication of treatment for childhood cancer. We evaluated the risk and risk factors for HF in a large European study of long-term survivors. Little is known of the effects of low doses of treatment, which is needed to improve current treatment protocols and surveillance guidelines. METHODS: This study includes the PanCareSurFup and ProCardio cohort of ≥ 5-year childhood cancer survivors diagnosed between 1940 and 2009 in seven European countries (N = 42,361). We calculated the cumulative incidence of HF and conducted a nested case-control study to evaluate detailed treatment-related risk factors. RESULTS: The cumulative incidence of HF was 2% (95% CI, 1.7 to 2.2) by age 50 years. The case-control study (n = 1,000) showed that survivors who received a mean heart radiation therapy (RT) dose of 5 to < 15 Gy have an increased risk of HF (odds ratio, 5.5; 95% CI, 2.5 to 12.3), when compared with no heart RT. The risk associated with doses 5 to < 15 Gy increased with exposure of a larger heart volume. In addition, the HF risk increased in a linear fashion with higher mean heart RT doses. Regarding total cumulative anthracycline dose, survivors who received ≥ 100 mg/m2 had a substantially increased risk of HF and survivors treated with a lower dose showed no significantly increased risk of HF. The dose-response relationship appeared quadratic with higher anthracycline doses. CONCLUSION: Survivors who received a mean heart RT dose of ≥ 5 Gy have an increased risk of HF. The risk associated with RT increases with larger volumes exposed. Survivors treated with < 100 mg/m2 total cumulative anthracycline dose have no significantly increased risk of HF. These new findings might have consequences for new treatment protocols for children with cancer and for cardiomyopathy surveillance guidelines.

Increased Cardiac Risk After a Second Malignant Neoplasm Among Childhood Cancer Survivors: A FCCSS Study.

Background: Childhood cancer survivors (CCS) are at an elevated risk of developing both a second malignant neoplasm (SMN) and cardiac disease. Objectives: This study sought to assess the excess of occurrence of cardiac disease after a SMN among CCS. Methods: Analyses included 7,670 CCS from the French Childhood Cancer Survivors Study cohort diagnosed between 1945 and 2000. To account for the time dependence of the occurrence of a SMN, we employed a landmark approach, considering an additive regression model for the cumulative incidence of cardiac disease. We estimated the effect of a SMN on the instantaneous risk of cardiac disease using a proportional cause-specific hazard model, considering a SMN as a time-dependent exposure. In both models, we adjusted for demographic and treatment information and considered death as a competing event. Results: In 7,670 CCS over a median follow-up of 30 years (IQR: 22-38 years), there were 378 cases of cardiac disease identified, of which 49 patients experienced a SMN. Patients who survived 25 years after their childhood cancer diagnosis and had a SMN in that time frame had a significantly increased cumulative incidence of cardiac disease, which was 3.8% (95% CI: 0.5% to 7.1%) higher compared with those without a SMN during this period. No SMN-induced excess of cardiac disease was observed at subsequent landmark times. SMNs were associated with a 2-fold increase (cause-specific HR: 2.0; 95% CI: 1.4-2.8) of cardiac disease. Conclusions: The occurrence of a SMN among CCS is associated with an increased risk of cardiac disease occurrence and risk at younger ages.

N-nitrosodimethylamine-Contaminated Valsartan and Risk of Cancer: A Nationwide Study of 1.4 Million Valsartan Users.

Background Since July 2018, numerous lots of valsartan have been found to be contaminated with N-nitrosodimethylamine (NDMA). We aimed to assess the association between exposure to valsartan products contaminated with NDMA and the risk of cancer. Methods and Results This study was based on data from the Système National des Données de Santé, which is a national database that includes all French residents' health-related expenses. The target population was consumers of valsartan between January 1, 2013 and December 31, 2017, aged between 40 and 80 years old. The association of exposure to contaminated valsartan with the occurrence of any malignancy and cancer by location was evaluated by fitting Cox proportional hazards models weighted by the inverse probability of treatment. A total of 1.4 million subjects without any history of cancer were included. A total of 986 126 and 670 388 patients were exposed to NDMA-contaminated and uncontaminated valsartan, respectively. The use of the NDMA-contaminated valsartan did not increase the overall risk of cancer (adjusted hazard ratio [aHR], 0.99 [95% CI, 0.98-1.0]). However, exposed patients had a higher risk of liver cancer (aHR, 1.12 [95% CI, 1.04-1.22]) and melanoma (aHR, 1.10 [95% CI, 1.03-1.18]). We estimated a mean of 3.7 and 5.8 extra cases per year per 100 000 person-years of liver cancer and melanoma, respectively. Conclusions Our study was the largest to date to examine cancer risks associated with exposure to NDMA-contaminated valsartan. Our findings suggest a slight increased risk of liver cancer and melanoma in patients exposed to NDMA in regularly taken medications.

Cohort profile: Risk and risk factors for female breast cancer after treatment for childhood and adolescent cancer: an internationally pooled cohort.

PURPOSE: The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer was established in 2018 to address gaps in knowledge of risk and risk factors for breast cancer subsequent to childhood/adolescent cancer by pooling individual patient data from seven cohorts. Initially, the pooled cohort will focus on three clinically relevant questions regarding treatment-related subsequent breast cancer risk in female survivors, which are the risk related to low-dose radiotherapy exposure to the chest, specific chemotherapy agents and attained age. PARTICIPANTS: The consortium database includes pooled data on 21 892 female survivors from seven cohorts in North America and Europe with a primary cancer diagnosis at <21 years of age, and survival ≥5 years from diagnosis. FINDINGS TO DATE: This is a newly established pooled study. The cohort profile summarised the data collected from each included cohort, including childhood cancer diagnosis information and treatment details (ie, radiotherapy fields and cumulative doses, and chemotherapy agents and cumulative doses for each agent). Included cohorts' follow-up started 1951-1981 and ended 2013-2021, respectively, for a median follow-up duration of 24.3 (IQR 18.0-32.8) years since primary cancer diagnosis. The median age at primary cancer diagnosis was 5.4 (IQR 2.5-11.9) years. And the median attained age at last follow-up was 32.2 (IQR 24.0-40.4) years. In all, 4240 (19.4%) survivors were treated with radiotherapy to the chest and 9308 (42.5%) with anthracyclines. At the end of the follow-up, 835 females developed a first subsequent breast cancer, including 635 invasive breast cancer only, 184 carcinomas in situ only (172 ductal carcinomas in situ and 12 lobular carcinomas in situ), and 16 with both an invasive and in situ diagnosis at the same moment. The cumulative incidences of subsequent breast cancer (both invasive and in situ) 25 and 35 years after primary cancer diagnosis were 2.2% and 6.2%, respectively. FUTURE PLANS: The consortium is intended to serve as a model and robust source of childhood/adolescent cancer survivor data for elucidating other knowledge gaps on subsequent breast cancer risk, and risk of other subsequent malignancies (including data on males) in the future.

Long-term hospitalisations in survivors of paediatric solid tumours in France.

The late effects of treatments for childhood cancers may lead to severe and multiple health conditions requiring hospitalisation. We aimed to estimate the hospitalisation rate among childhood cancer survivors (CCS) in France, to compare them with the general population and to investigate the associated factors. We matched total of 5439 5-year solid CCS diagnosed before the age of 21 between 1945 and 2000 by sex, birth year and region of residence to 386,073 individuals of the French general population. After linkage with the national hospital discharge database, we estimated the relative hospitalisation rate (RHR), the absolute excess risks (AERs) and the relative bed-day ratio (RBDR) during 2006-2018. We used generalised linear models to estimate associations between hospitalisation and survivor characteristics. Overall, the RHR was 2.49 (95% confidence interval [CI] 2.46-2.52) and the RBDR was 3.49 (95% CI 3.46-3.51). We found that neoplasm-related hospitalisations had the highest AER (105.8 per 1000 person-years), followed by genitourinary system diseases (34.4 per 1000 person-years) and cardiovascular diseases (19.2 per 1000 person-years). In adjusted analysis, CCS treated with chemotherapy (risk ratio [RR] 1.62, 95% CI 1.53-1.70), radiotherapy (RR 2.11, 95% CI 1.99-2.24) or both (RR 2.59, 95% CI 2.46-2.73) had a higher risk of hospitalisation than the ones who had not received any of these treatments. CCS treated during the past decades by chemotherapy and/or radiotherapy now had a higher hospitalisation risk for all main categories of diagnosis than the general population. Prevention strategies and medical surveillance programmes may promote a long-term decrease in the hospitalisation rate among CSS.