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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.

Radiotherapy has evolved from 2-dimensional conventional radiotherapy (2D-RT) to 3-dimensional planned radiotherapy (3D-RT). Because 3D-RT improves conformity, an altered late health outcomes risk profile is anticipated. Here, we systematically reviewed the current literature on late toxicity after 3D-RT in children treated for cancer. PubMed was searched for studies describing late toxicity after 3D-RT for childhood cancer (below 21 y). Late toxicity was defined as somatic health outcomes occurring ≥90 days after treatment. We identified 13 eligible studies, describing most frequently head/neck area tumors. Included studies reported on crude frequencies of late toxicities including subsequent tumors and conditions of organ systems. Three studies offered a global assessment of the full spectrum of late toxicity; one study compared toxicities after 2D-RT and 3D-RT. Incidence rates were typically not provided. Heterogeneity in study characteristics, small study sizes and short follow-up times precluded multivariable modeling and pooling of data. In conclusion, among the first pediatric cohorts treated with 3D-RT, a broad variety of late toxicity is reported; precise estimates of incidence, and contributions of risk factors are unclear. Continued systematic evaluation of well-defined health outcomes in survivors treated with 3D-RT, including proton therapy, is needed to optimize evidence-based care for children with cancer and survivors.

BACKGROUND Breast cancer is a well-recognised late adverse effect in female childhood cancer survivors (CCSs), especially after chest radiotherapy; information on subsequent male breast cancer (SMBC) is limited. We summarised the existing evidence on SMBC after childhood cancer in a systematic review��and investigated the risk of SMBC among males in a Pan-European cohort. METHODS We searched Medline/PubMed for cohort studies and case reports/series that assessed SMBC after childhood cancer (���21 years). Furthermore, we analysed data on SMBC in the PanCareSurFup cohort, reporting standardised incidence ratios (SIRs), absolute excess risks (AERs), and 5- and 10-year survival rates. RESULTS The systematic review included 38 of 7080 potentially eligible articles. Cohort-specific SMBC frequencies were 0-0.40% (31 studies). SMBC occurred after a follow-up ranging from 24.0 to 42.0 years. Nine case reports/series described 11 SMBC cases, occurring 11.0-42.5 years after primary childhood cancer. In the PanCareSurFup cohort (16 SMBC/37,738 males; 0.04%), we observed a 22.3-fold increased risk of SMBC relative to the general male population (95% CI 12.7-36.2; absolute excess risk/100,000 person-years: 2.3, 95% CI 1.3-3.7). The five- and ten-year survival rates after SMBC diagnosis were 60.3% (95% CI 35.6%-85.0%) and 43.0% (95% CI 16.1%-69.9%), respectively. Clear evidence of risk factors did not emerge from these comprehensive efforts. CONCLUSIONS Compared to the general population, male CCSs have an elevated risk of developing subsequent breast cancer, although the absolute risk is low. Health care providers should be aware of this rare yet serious late effect; male CCSs with symptoms potentially related to SMBC warrant careful examination.

Contains fulltext : 291345.pdf (Publisher’s version ) (Open Access) BACKGROUND: Adverse late health outcomes after multimodal treatment for pediatric cancer are diverse and of prime interest. Currently available evidence and survivorship care guidelines are largely based on studies addressing side-effects of two dimensional planned radiotherapy. AIMS: The Dutch pediatric 3D-planned radiotherapy (3D-RT) study aims to gain insight in the long-term health outcomes among children who had radiotherapy in the 3D era. Here, we describe the study design, data-collection methods, and baseline cohort characteristics. METHODS AND RESULTS: The 3D-RT study represents an expansion of the Dutch Childhood Cancer Survivor study (DCCSS) LATER cohort, including pediatric cancer patients diagnosed during 2000-2012, who survived at least 5 years after initial diagnosis and 2 years post external beam radiotherapy. Individual cancer treatment parameters were obtained from medical files. A national infrastructure for uniform collection and archival of digital radiotherapy files (Computed Tomography [CT]-scans, delineations, plan, and dose files) was established. Health outcome information, including subsequent tumors, originated from medical records at the LATER outpatient clinics, and national registry-linkage. With a median follow-up of 10.9 (interquartile range [IQR]: 7.9-14.3) years after childhood cancer diagnosis, 711 eligible survivors were identified. The most common cancer types were Hodgkin lymphoma, medulloblastoma, and nephroblastoma. Most survivors received radiotherapy directed to the head/cranium only, the craniospinal axis, or the abdominopelvic region. CONCLUSION: The 3D-RT study will provide knowledge on the risk of adverse late health outcomes and radiation-associated dose-effect relationships. This information is valuable to guide follow-up care of childhood cancer survivors and to refine future treatment protocols. 01 februari 2023

Contains fulltext : 291510.pdf (Publisher’s version ) (Open Access) BACKGROUND: Childhood cancer survivors face late health problems; despite advances in research, details on risk remain unclear. We describe the methodological aspects of the Dutch Childhood Cancer Survivor Study (DCCSS) cross-sectional clinical study (LATER 2 study). PROCEDURE: From the multi-center DCCSS LATER cohort of 6165 five-year survivors diagnosed during 1963-2001, we invited 4735 eligible survivors in 2016, as well as siblings and parents of survivors. Gaps in evidence identified during development of surveillance guidelines were translated into clinical research questions for 16 outcome-specific subprojects. The regular care visit to the LATER outpatient clinic forms the backbone of outcome assessment complemented with research-defined measurements (physical examination, clinical tests, questionnaires). Furthermore, blood/saliva samples were taken for deoxyribonucleic acid (DNA) extraction. RESULTS: In total, 2519 (53.2%) survivors participated in the LATER 2 study. When comparing participants with nonparticipants, we observed that males, CNS survivors, and those treated with surgery only were less likely to participate. Of the participating survivors, 49.3% were female. Median time since childhood cancer diagnosis was 26.9 years (range 14.8-54.7 years) and median attained age was 34.4 years (range 15.4-66.6 years). CONCLUSIONS: The high-quality data generated in the LATER 2 study will provide valuable insights into risks of and risk factors for clinical and physical and psychosocial health outcomes and factors for early recognition of those health outcomes in long-term childhood cancer survivors. This will contribute to fill in important gaps in knowledge and improve the quality of life and care for childhood cancer survivors.

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., + ID der Publikation: unilu_61255 + Sprache: Englisch + Letzte Aktualisierung: 2022-11-03 12:45:00

Contains fulltext : 248803.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cancer-related fatigue is a debilitating late effect after treatment for childhood cancer. The prevalence of fatigue in childhood cancer survivors (CCSs) and associated factors for fatigue has varied widely in previous studies. Two important aspects of cancer-related fatigue, its severity and chronicity, are often not assessed. This study investigated the prevalence of, and risk factors for, severe chronic fatigue (CF) in a national cohort of Dutch CCSs. METHODS: In this study, 2810 CCSs (5-year survivors of all childhood malignancies diagnosed between 1963 and 2001 with a current age of 12-65 years) and 1040 sibling controls were included. CF was assessed with the Short Fatigue Questionnaire and was defined as a score ≥ 18 and persistence of fatigue for ≥6 months. Cancer- and treatment-related characteristics, current health problems, and demographic and lifestyle variables were assessed as potential risk factors for CF via multivariable logistic regression analyses. RESULTS: In adult CCSs and sibling controls (≥18 years old), the prevalence of CF was 26.1% and 14.1%, respectively (P < .001). In adolescent CCSs and sibling controls (2, 2.20; 95% CI, 1.50-3.21), and a central nervous system diagnosis (OR, 1.74; 95% CI, 1.17-2.60) were significantly associated with CF in adult CCSs. CONCLUSIONS: This study shows that CCSs, regardless of their cancer diagnosis, report CF more often than sibling controls. This study provides new evidence for the prevalence of fatigue in CCSs.

Background: Meningiomas are the most frequent brain tumours occurring after pediatric cranial radiotherapy (CrRT). Data on course of disease, to inform clinical management of meningiomas, are sparse. This study reports the clinical characteristics of histologically confirmed meningiomas in childhood cancer survivors (CCS) in the Netherlands. Methods: In total, 6015 CCS from the Dutch Long-Term Effects After Childhood Cancer (LATER) cohort were eligible, including 1551 with prior CrRT. These CCS were diagnosed with cancer age

Exposure to cranial radiotherapy is associated with an increased risk of subsequent CNS neoplasms among childhood, adolescent, and young adult (CAYA) cancer survivors. Surveillance for subsequent neoplasms can translate into early diagnoses and interventions that could improve cancer survivors' health and quality of life. The practice guideline presented here by the International Late Effects of Childhood Cancer Guideline Harmonization Group was developed with an evidence-based method that entailed the gathering and appraisal of published evidence associated with subsequent CNS neoplasms among CAYA cancer survivors. The preparation of these guidelines showed a paucity of high-quality evidence and highlighted the need for additional research to inform survivorship care. The recommendations are based on careful consideration of the evidence supporting the benefits, risks, and harms of the surveillance interventions, clinical judgment regarding individual patient circumstances, and the need to maintain flexibility of application across different health-care systems. Currently, there is insufficient evidence to establish whether early detection of subsequent CNS neoplasms reduces morbidity and mortality, and therefore no recommendation can be formulated for or against routine MRI surveillance. The decision to start surveillance should be made by the CAYA cancer survivor and health-care provider after careful consideration of the potential harms and benefits of surveillance for CNS neoplasms, including meningioma.

The authors' objective is to provide a brief update on recent advances in knowledge relating to subsequent primary neoplasms developing in survivors of childhood cancer. This includes a summary of established large-scale cohorts, risks reported, and contrasts with results from recently established large-scale cohorts of survivors of adolescent and young adult cancer. Recent evidence is summarized concerning the role of radiotherapy and chemotherapy for childhood cancer and survivor genomics in determining the risk of subsequent primary neoplasms. Progress with surveillance, screening, and clinical follow-up guidelines is addressed. Finally, priorities for future research are outlined.

PurposeThe 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.ParticipantsThe consortium database includes pooled data on 21 892 female survivors from seven cohorts in North America and Europe with a primary cancer diagnosis at Findings to dateThis 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 plansThe 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.

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.

Objectives: The aim of this study was to identify the prevalence of and independent risk factors for long-term effects of childhood cancer treatment on the dentition and oral health in childhood cancer survivors (CCSs). Methods: This cross-sectional study is part of the Dutch Childhood Cancer Survivor Study (DCCSS) LATER 2. CCSs were diagnosed with cancer between 1963 and 2001. This study focuses on survey data of 154 CCSs on whom information about their oral health was received from their dentists (71.3%). Descriptive statistics and univariable and multivariable Poisson regression analyses were performed to determine the association between treatment characteristics and oral health data. Results: Of the study group, 36.3% had at least one DDD. The most prevalent DDDs were short-root anomaly (14.6%), agenesis (14.3%), and microdontia (13.6%). Risk factors for at least one DDD were younger age at diagnosis (&lt, 3 years) and dose-dependent alkylating agent therapy. Conclusions: This study provides more insight into risk factors for oral health problems in Dutch CCSs. This information is essential in order to improve early detection, prevention, dental care, and quality of life. Further studies are needed in order to better define dose-related radiotherapy exposure of the developing teeth in correlation with oral health problems.

Neuroblastoma survivors have an increased risk of unfavorable long-term health outcomes, of which developing subsequent neoplasms is one of the most serious. We aimed to provide an overview of the current knowledge on the risk of subsequent neoplasms in neuroblastoma survivors. We conducted a systematic literature search in Medline/Pubmed (01-01-1945-13-01-2022) to identify studies that reported on ≥ 100 neuroblastoma survivors and assessed subsequent neoplasms as an outcome. We identified 410 potentially eligible articles, of which we eventually included 13 reports. All articles described retrospective cohorts with sizes varying from 145 to 5,987 neuroblastoma survivors. Within these cohorts 0.7% - 17.2% of the survivors developed a subsequent neoplasm. A wide variety of types of subsequent malignant and non-malignant neoplasms were observed, of which thyroid carcinoma and acute myeloid leukemia were most frequently reported. The risk of developing a subsequent neoplasm was 2.8 to 10.4 times higher in neuroblastoma survivors than in the general population. Although no statistically significant risk factors for subsequent neoplasms were observed in multivariable analyses, high-risk group survivors, women and those treated with radiotherapy seemed to have a higher risk. In conclusion, the studies in this systematic review consistently show that neuroblastoma survivors are at elevated risk of developing subsequent neoplasms. Future research should further explore risk factors for subsequent neoplasms in neuroblastoma survivors, so future treatment protocols and follow-up care can be improved.

The authors' objective is to provide a brief update on recent advances in knowledge relating to subsequent primary neoplasms developing in survivors of childhood cancer. This includes a summary of established large-scale cohorts, risks reported, and contrasts with results from recently established large-scale cohorts of survivors of adolescent and young adult cancer. Recent evidence is summarized concerning the role of radiotherapy and chemotherapy for childhood cancer and survivor genomics in determining the risk of subsequent primary neoplasms. Progress with surveillance, screening, and clinical follow-up guidelines is addressed. Finally, priorities for future research are outlined.

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.

BackgroundSurvivors of childhood cancer are at risk of subsequent primary neoplasms (SPNs), but the risk of developing specific digestive SPNs beyond age 40 years remains uncertain. We investigated risks of specific digestive SPNs within the largest available cohort worldwide.MethodsThe PanCareSurFup cohort includes 69 460 five-year survivors of childhood cancer from 12 countries in Europe. Risks of digestive SPNs were quantified using standardised incidence ratios (SIRs), absolute excess risks and cumulative incidence.Results427 digestive SPNs (214 colorectal, 62 liver, 48 stomach, 44 pancreas, 59 other) were diagnosed in 413 survivors. Wilms tumour (WT) and Hodgkin lymphoma (HL) survivors were at greatest risk (SIR 12.1; 95% CI 9.6 to 15.1; SIR 7.3; 95% CI 5.9 to 9.0, respectively). The cumulative incidence increased the most steeply with increasing age for WT survivors, reaching 7.4% by age 55% and 9.6% by age 60 years (1.0% expected based on general population rates). Regarding colorectal SPNs, WT and HL survivors were at greatest risk; both seven times that expected. By age 55 years, 2.3% of both WT (95% CI 1.4 to 3.9) and HL (95% CI 1.6 to 3.2) survivors had developed a colorectal SPN—comparable to the risk among members of the general population with at least two first-degree relatives affected.ConclusionsColonoscopy surveillance before age 55 is recommended in many European countries for individuals with a family history of colorectal cancer, but not for WT and HL survivors despite a comparable risk profile. Clinically, serious consideration should be given to the implementation of colonoscopy surveillance while further evaluation of its benefits, harms and cost-effectiveness in WT and HL survivors is undertaken.

Item does not contain fulltext We systematically reviewed outcome assessment methods, outcome classification, and severity grading of reported outcomes in studies investigating the burden of physical long-term morbidity in childhood cancer survivors (CCS). A MEDLINE and EMBASE search identified 56 studies reporting on three or more types of health conditions in 5-year CCS, for which information was extracted on outcome types and classification, methods of outcome ascertainment, and severity grading. There was substantial variability in classification and types of health conditions reported and in methods of outcome ascertainment. Only 59% of the included studies applied severity grading, mainly the common terminology criteria of adverse events. This large variation in assessment and definition of the burden of physical long-term morbidity in CCS challenges interpretation, comparison, and pooling data across studies. Global collaboration is needed to standardize assessments and harmonize definitions of long-term physical morbidity and associated outcomes in childhood cancer survivorship research.

Background Survivors of childhood cancers are at risk of developing subsequent primary leukaemias (SPLs), but the long-term risks beyond 20 years of treatment are still unclear. We investigated the risk of SPLs in five-year childhood cancer survivors using a large-scale pan-European (PanCareSurFup) cohort and evaluated variations in the risk by cancer and demographic factors. Methods This largest-ever assembled cohort comprises 69,460 five-year childhood cancer survivors from 12 European countries. Standardised incidence ratios (SIRs) and absolute excess risks (AERs) were calculated. Results One hundred fifteen survivors developed an SPL including 86 myeloid leukaemias (subsequent primary myeloid leukaemias [SPMLs]), 17 lymphoid leukaemias and 12 other types of leukaemias; of these SPLs, 31 (27%) occurred beyond 20 years from the first childhood cancer diagnosis. Compared with the general population, childhood cancer survivors had a fourfold increased risk (SIR = 3.7, 95% confidence interval [CI]: 3.1 to 4.5) of developing leukaemia, and eight leukaemias per 100,000 person-years (AER = 7.5, 95% CI: 6.0 to 9.2) occurred in excess of that expected. The risks remained significantly elevated beyond 20 years from the first primary malignancy (SIR = 2.4, 95% CI: 1.6 to 3.4). Overall, the risk ratio for SPML (SIR = 5.8, 95% CI: 4.6 to 7.1) was higher than that for other SPLs. Conclusions We demonstrate that beyond 20 years after childhood cancer diagnosis, survivors experience an increased risk for SPLs compared with that expected from the general population. Our findings highlight the need for awareness by survivors and their healthcare providers for potential risk related to SPL.

Contains fulltext : 204846.pdf (Publisher’s version ) (Closed access) BACKGROUND: Childhood cancer survivors (CCS) are at risk of developing long-term morbidity, which is likely to be presented to a primary care physician (PCP). Therefore, insight into CCS's PCP-based health care use is needed. We investigated the volume and underlying health problems of PCP-based health care use and the determinants for PCP-based health care use in CCS. PROCEDURE: Data from a Dutch cohort of 6018 eligible five-year CCS were linked to the Nivel Primary Care database, which contains detailed data from a representative sample of 10% of all Dutch PCPs. Per CCS, two matched controls were selected. Negative binomial regression was performed to compare the annual number of contacts between CCS and controls, and to identify determinants for PCP-based care use among CCS. RESULTS: This study included 602 CCS and 1204 controls. CCS were 1.3 times more likely to contact their PCP than controls (95% CI, 1.2-1.5), up to 1.5 times at attained age over 40 years (95% CI, 1.2-1.8). CCS were 4.9 times more likely to contact their PCP for new malignancies, 3.1 for hematological conditions, and 2.8 for endocrine conditions. Female sex, higher attained age, and treatment with radiotherapy were determinants for having more PCP contacts. CONCLUSIONS: PCPs play an important role in care for CCS. CCS use more PCP-based care than matched controls, mainly for severe conditions such as malignancies, hematological, and endocrine conditions. Our results emphasize the importance of disseminating the current knowledge on long-term morbidity in CCS and on their optimal follow-up care among PCPs.

Background: Childhood cancer survivors (CCS) are at increased risk of developing subsequent malignant neoplasms, including gastrointestinal (GI) cancer. We performed a systematic review to summarize all available literature on the risk of, risk factors for, and outcome after subsequent GI cancer among CCS. Methods: A systematic search of the literature databases Medline/PubMed (1945-2014) and Embase (1947-2014) was performed to identify studies that consisted of >= 1000 CCS and assessed incidence of or mortality from subsequent GI cancer as an outcome. Results: A total of 45 studies were included. Studies that reported risk measures for subsequent GI cancer compared to the general population showed a 3.2 to 9.7-fold elevated risk in cohort studies including all childhood cancer types. Abdominal radiotherapy was associated with an increased risk of subsequent GI cancer in all four studies that assessed this risk. Survivors who had received procarbazine and platinum agents were also suggested to be at increased risk. Conclusion: Abdominal radiotherapy is a risk factor for developing a subsequent GI cancer. Few studies examined detailed treatment-related risk factors and most studies had small number of GI cancer cases. Therefore, no conclusions could be drawn on the effect of time since childhood cancer on GI cancer risk and on outcome after a subsequent GI cancer. Additional research is necessary to further explore risk factors for and outcome after a subsequent GI cancer, and to systematically evaluate the harms and benefits of GI screening among high-risk survivors in order to give sound screening recommendations. (C) 2015 Elsevier Ltd. All rights reserved.

Background: Childhood cancer survivors are at risk of subsequent primary soft-tissue sarcomas (STS), but the risks of specific STS histological subtypes are unknown. We quantified the risk of STS histological subtypes after specific types of childhood cancer.Methods: We pooled data from 13 European cohorts, yielding a cohort of 69 460 five-year survivors of childhood cancer. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated.Results: Overall, 301 STS developed compared with 19 expected (SIR = 15.7, 95% confidence interval [CI] = 14.0 to 17.6). The highest standardized incidence ratios were for malignant peripheral nerve sheath tumors (MPNST; SIR = 40.6, 95% CI = 29.6 to 54.3), leiomyosarcomas (SIR = 29.9, 95% CI = 23.7 to 37.2), and fibromatous neoplasms (SIR = 12.3, 95% CI = 9.3 to 16.0). SIRs for MPNST were highest following central nervous system tumors (SIR = 80.5, 95% CI = 48.4 to 125.7), Hodgkin lymphoma (SIR = 81.3, 95% CI = 35.1 to 160.1), and Wilms tumor (SIR = 76.0, 95% CI = 27.9 to 165.4). Standardized incidence ratios for leiomyosarcoma were highest following retinoblastoma (SIR = 342.9, 95% CI = 245.0 to 466.9) and Wilms tumor (SIR = 74.2, 95% CI = 37.1 to 132.8). AERs for all STS subtypes were generally low at all years from diagnosis (AER < 1 per 10 000 person-years), except for leiomyosarcoma following retinoblastoma, for which the AER reached 52.7 (95% CI = 20.0 to 85.5) per 10 000 person-years among patients who had survived at least 45 years from diagnosis of retinoblastoma.Conclusions: For the first time, we provide risk estimates of specific STS subtypes following childhood cancers and give evidence that risks of MPNSTs, leiomyosarcomas, and fibromatous neoplasms are particularly increased. While the multiplicative excess risks relative to the general population are substantial, the absolute excess risk of developing any STS subtype is low, except for leiomyosarcoma after retinoblastoma. These results are likely to be informative for both survivors and health care providers.

Introduction: We investigate the risks of subsequent primary bone cancers after childhood and adolescent cancer in 12 European countries. For the first time, we satisfactorily address the risks beyond 40 years from diagnosis and beyond 40 years of age among all survivors.Methods: This largest-ever assembled cohort comprises 69 460 five-year survivors of cancer diagnosed before age 20 years. Standardized incidence ratios, absolute excess risks, and multivariable-adjusted relative risks and relative excess risks were calculated. All statistical tests were two-sided.Results: Overall, survivors were 21.65 times (95% confidence interval = 18.97 to 24.60 times) more likely to be diagnosed with a subsequent primary bone cancer than expected from the general population. The greatest excess numbers of bone cancers were observed after retinoblastoma, bone sarcoma, and soft tissue sarcoma. The excess number of bone cancers declined linearly with both years since diagnosis and attained age (all P < .05). Beyond 40 years from diagnosis and age 40 years, there were at most 0.45 excess bone cancers among all survivors per 10 000 person-years at risk; beyond 30 years from diagnosis and age 30 years, there were at most 5.02 excess bone cancers after each of retinoblastoma, bone sarcoma, and soft tissue sarcoma, per 10 000 person-years at risk.Conclusions: For all survivors combined and the cancer groups with the greatest excess number of bone cancers, the excess numbers observed declined with both age and years from diagnosis. These results provide novel, reliable, and unbiased information about risks and risk factors among long-term survivors of childhood and adolescent cancer.

Although increased risk of acute myeloid leukemia (AML) has been observed after chemotherapy and radiotherapy, less is known about radiotherapy-related risks of specific AML subtypes and other specific myeloid neoplasms. We used the US population-based cancer registry data to evaluate risk of myeloid neoplasms among three cohorts of cancer survivors initially treated with radiotherapy only. We included 1-year survivors of first primary thyroid (radioiodine only, stages I–IV; N = 49 879), prostate (excluding stage IV; N = 237 439), or uterine corpus cancers (stage I–II; N = 16 208) diagnosed during 2000–2013. We calculated standardized incidence ratios (SIRs) and excess absolute risks (EARs). Thyroid cancer survivors had significantly elevated risks of total AML (SIR = 2.77, 95% CI: 1.99–3.76), AML with cytogenetic abnormalities (SIR = 3.90, 95% CI: 1.57–8.04), AML with myelodysplasia-related changes (SIR = 2.87, 95% CI: 1.05–6.25), and BCR-ABL1-positive chronic myelogenous leukemia (CML) (SIR = 5.38, 95% CI: 2.58–9.89). Irradiated prostate and uterine corpus cancer survivors were at elevated risk for total AML (SIR = 1.14, 95% CI: 1.03–1.27 and SIR = 1.77, 95% CI: 1.01–2.87, respectively), AML with cytogenetic abnormalities (SIR = 2.52, 95% CI: 1.84–3.37 and SIR = 7.21, 95% CI: 2.34–16.83, respectively), and acute promyelocytic leukemia (SIR = 3.20, 95% CI: 2.20–4.49 and SIR = 8.88, 95% CI: 2.42–22.73, respectively). In addition, prostate cancer survivors were at increased risk of BCR-ABL1-positive CML (SIR = 2.11, 95% CI: 1.52–2.85). Our findings support the importance of diagnostic precision in myeloid neoplasm classification since susceptibility following radiotherapy may vary by myeloid neoplasm subtype, thereby informing risk/benefit discussions in first primary cancer treatment.

Childhood cancer survivors (CCS) are at increased risk of developing colorectal cancer (CRC) compared to the general population, especially those previously exposed to abdominal or pelvic radiation therapy (APRT). However, the benefits and costs of CRC screening in CCS are unclear. In this study, we evaluated the cost-effectiveness of early-initiated colonoscopy screening in CCS.We adjusted a previously validated model of CRC screening in the US population (MISCAN-Colon) to reflect CRC and other-cause mortality risk in CCS. We evaluated 91 colonoscopy screening strategies varying in screening interval, age to start, and age to stop screening for all CCS combined and for those treated with or without APRT. Primary outcomes were CRC deaths averted (compared to no screening) and incremental cost-effectiveness ratios (ICERs). A willingness-to-pay threshold of $100 000 per life-years gained (LYG) was used to determine the optimal screening strategy.Compared to no screening, the US Preventive Services Task Force's average risk screening schedule prevented up to 73.2% of CRC deaths in CCS. The optimal strategy of screening every 10 years from age 40 to 60 years averted 79.2% of deaths, with ICER of $67 000/LYG. Among CCS treated with APRT, colonoscopy every 10 years from age 35 to 65 years was optimal (CRC deaths averted: 82.3%; ICER: $92 000/LYG), whereas among those not previously treated with APRT, screening from age 45 to 55 years every 10 years was optimal (CRC deaths averted: 72.7%; ICER: $57 000/LYG).Early initiation of colonoscopy screening for CCS is cost-effective, especially among those treated with APRT.

Item does not contain fulltext The increasing exposure to electromagnetic fields (EMFs) has raised concern, as increased exposure may result in an increased risk of childhood leukemia (CL). Besides a short introduction of CL and EMF, our article gives an evaluation of the evidence of a causal relation between EMF and CL by critically appraising the epidemiological and biological evidence. The potential impact is also estimated by the population attributable risk. The etiology of CL is largely unknown, but is probably multifactorial. EMF may be one of the environmental exposures involved. Three pooled analyses of case-control studies showed a 1.4- to 1.7-fold increased CL risk for extremely low-frequency EMF (ELF-EMF) exposure levels above 0.3 muT. Several biases may have played a role in these studies, but are unlikely to fully explain the increased risk. For effects of radiofrequency ELF evidence is lacking. None of the proposed biological mechanisms by which ELF-EMF might cause CL have been confirmed. The estimated overall population attributable risk was 1.9%, with the highest estimates in Northern America and Brazil (4.2% and 4.1%, respectively). The potential impact of EMF exposure on public health is probably limited, although in some countries exposure might be relatively high and thus might have a more substantial impact. We recommend nationwide surveys to gain more insight into the contemporary exposure levels among children. Reducing exposure from power lines near densely populated areas and schools is advised. Future epidemiological studies should focus on limiting bias.

Introduction. Treatment-related acute myeloid leukemia/myelodysplastic syndrome (tAML/MDS) is a rare but often fatal complication of systemic therapy for primary malignancy. Leukemogenicity of specific agents is variable, with particularly high risks associated with platinum-containing agents, certain alkylating agents, topoisomerase II inhibitors, and purine analogs. Current treatment practices increasingly include (neo)adjuvant and multiple courses of systemic therapy for a number of first primary malignancies. However, no large-scale study has quantified risks of tAML/MDS and other myeloid neoplasms after chemotherapy in the modern treatment era. Methods. We identified a cohort of 746,007 adults who were initially treated with chemotherapy and survived ≥1 year following diagnosis with first primary malignancy during 2000-2012, as reported to 17 US population-based cancer registries from the Surveillance, Epidemiology, and End Results program. Risks for second primary AML/MDS, chronic myeloid leukemia (CML), and other myeloproliferative neoplasms (MPNs) and MDS/MPNs were compared to that expected in the general population (based on age-, race-, sex- and calendar period-specific incidence rates) using standardized incidence ratios (SIRs). Results. tAML/MDS was identified in 2071 individuals following chemotherapy, four times more than expected based on general population rates (SIR=4.1, 95%CI=3.9-4.2). We identified novel elevations in tAML/MDS risk after chemotherapy for most gastrointestinal malignancies, including the oral cavity/pharynx (N=45, SIR=2.6, 95%CI=1.9-3.5), esophagus (N=28, SIR=4.3, 95%CI=2.9-6.2), liver (N=10, SIR=2.6, 95%CI=1.2-4.8), stomach (N=22, SIR=2.7, 95%CI=1.7-4.0), rectum (N=65, SIR=1.5, 95%CI=1.2-1.9), and anus (N=22, SIR=3.6, 95%CI=2.3-5.5), but not colon (N=67, SIR=1.1, 95%CI=0.8-1.3). Novel increased risks of tAML/MDS also were observed after chemotherapy for cancers of the pancreas (N=15, SIR=3.3, 95%CI=1.8-5.4), larynx (N=20, SIR=4.2, 95%CI=2.6-6.5), bladder (N=30, SIR=1.8, 95%CI=1.2-2.6), and melanoma (N=4, SIR=3.7, 95%CI=1.0-9.6) Similar to previous studies, tAML/MDS occurred most commonly after female breast cancer (N=543, SIR=4.1, 95%CI=3.8-4.5), non-Hodgkin lymphoma (NHL; N=515, SIR=7.3, 95%CI=6.7-7.9), and lung cancer (N=185, SIR=4.1, 95%CI=3.5-4.7). We further confirmed previous observations of strikingly elevated risks of tAML/MDS after chemotherapy for cancers of the bone (N=10, SIR=35.1, 95%CI=16.9-64.6), testis (N=18, SIR=15.6, 95%CI=9.2-24.6), and soft-tissue (N=20, SIR=12.6, 95%CI=7.7-19.4), and more modestly elevated risks of tAML/MDS after chemotherapy for cancers of brain (N=18, SIR-7.8, 95%CI=4.6-12.4), ovary (N=84, SIR=5.5, 95%CI=4.3-6.7), endometrium (N=28, SIR=4.4, 95%CI=2.9-6.3), cervix (N=22, SIR=4.4, 95%CI=2.8-6.6), and prostate (N=15, SIR=2.7, 95%CI=1.5-4.4), as well as Hodgkin lymphoma (N=54, SIR=8.7, 95%CI=6.6-11.4), chronic lymphocytic leukemia (N=52, SIR=7.7, 95%CI=5.8-10.2), and myeloma (N=102, SIR=6.3, 95%CI=5.1-7.6). Risks were non-significantly heightened with radiotherapy plus chemotherapy for breast, lung, and stomach cancers compared with chemotherapy alone. Elevated risks also were observed for CML after chemotherapy for lung cancer (N=12, SIR=2.5, 95%CI=1.3-4.4), breast cancer (N=35, SIR=1.8, 95%CI=1.3-2.5), and NHL (N=16, SIR=2.1, 95%CI=1.2-3.4), and for chronic myelomonocytic leukemia after chemotherapy for breast cancer (N=15, SIR=3.0, 95%CI=1.7-5.0) and NHL (N=16, SIR=4.2, 95%CI=2.4-6.9). In contrast, risks were not increased for other MPNs after chemotherapy for any first primary malignancy. Conclusions. Despite the availability of modern cancer chemotherapy and targeted agents, risks of tAML/MDS are elevated across a broad spectrum of first primary cancers and extend to other myeloid neoplasms. Risks are consistent with those expected from expanded use of leukemogenic systemic therapy, particularly for specific cancers, such as cervical cancer, that are commonly treated with platinum-based regimens. More research is needed to quantify risks associated with specific agents and doses in the (neo)adjuvant and treatment setting. Risks for treatment-related myeloid neoplasms should be weighed against benefits of systemic therapy. Disclosures No relevant conflicts of interest to declare.

Item does not contain fulltext BACKGROUND: Since its introduction, there has been controversy about the use of locking plates in the treatment of proximal humeral fractures. Have they really improved the functional outcome after a proximal humeral fracture or should nonsurgical treatment have a more prominent role? In order to evaluate our hypothesis that nonsurgical treatment for proximal humerus fractures should be the first choice of treatment, a matched controlled cohort study was conducted to compare the midterm (>1 year) functional and radiologic outcome of a group of patients treated with a locking plate and a matched group of patients treated nonsurgically. Complications in each group of patients were evaluated. MATERIALS AND METHODS: Through direct matching, 17 patients (1 bilateral fracture) treated with a locking plate were matched to 18 patients treated nonsurgically. Medical records and radiographs were reviewed retrospectively to obtain relevant patient related data and fracture type according to Neer classification (i.e. 2-, 3- and 4-part fractures). At the time of clinical follow-up, EQ-5D, American Shoulder and Elbow Surgeons (ASES) score, visual analog pain (VAS) pain and VAS satisfaction scores were completed. Active range of motion was tested. New radiographs were made to evaluate fracture healing, complications and, in the locking plate group, the position of the plate and screws. RESULTS: No significant differences were found in the characteristics of the patient groups. A significant difference in range of motion was found in favor of the nonsurgically treated patients. Results of ASES and patient satisfaction scores were also tending toward nonsurgical treatment. Furthermore, the complication rate was higher with locking plate treatment. Patients treated with a locking plate needed significantly more additional treatment on their injured shoulder (P = 0.005). DISCUSSION: This study's main limitation was the fact that the choice of initial fracture management was based on clinical judgement, as well as patient's fitness for surgery and therefore not randomized. By matching for fracture type this bias was largely overcome. Surgical treatment had a higher complication rate, requiring more additional treatment, which was often related to the initial surgery. Improving surgical technique could possibly lead to better outcomes for the surgically treated patients. In addition to the more favorable outcomes, nonsurgical treatment is also a more cost effective treatment. CONCLUSION: Nonsurgical treatment should have a more prominent role in the treatment of proximal humeral fractures.