Late mortality of European 5‐year survivors of childhood or adolescent cancer has dropped over the last 60 years, but excess mortality persists. There is little information concerning secular trends ...in cause‐specific mortality among older European survivors. PanCareSurFup pooled data from 12 cancer registries and clinics in 11 European countries from 77 423 five‐year survivors of cancer diagnosed before age 21 between 1940 and 2008 followed for an average age of 21 years and a total of 1.27 million person‐years to determine their risk of death using cumulative mortality, standardized mortality ratios (SMR), absolute excess risks (AER), and multivariable proportional hazards regression analyses. At the end of follow‐up 9166 survivors (11.8%) had died compared to 927 expected (SMR 9.89, 95% confidence interval 95% CI 9.69‐10.09), AER 6.47 per 1000 person‐years, (95% CI 6.32‐6.62). At 60 to 68 years of attained age all‐cause mortality was still higher than expected (SMR = 2.41, 95% CI 1.90‐3.02). Overall cumulative mortality at 25 years from diagnosis dropped from 18.4% (95% CI 16.5‐20.4) to 7.3% (95% CI 6.7‐8.0) over the observation period. Compared to the diagnosis period 1960 to 1969, the mortality hazard ratio declined for first neoplasms (P for trend <.0001) and for infections (P < .0001); declines in relative mortality from second neoplasms and cardiovascular causes were less pronounced (P = .1105 and P = .0829, respectively). PanCareSurFup is the largest study with the longest follow‐up of late mortality among European childhood and adolescent cancer 5‐year survivors, and documents significant mortality declines among European survivors into modern eras. However, continuing excess mortality highlights survivors' long‐term care needs.
What's new?
Children and adolescents who survive cancer have increased mortality rates compared with the general population. Here, the authors investigated trends in mortality among European cancer survivors 5 or more years after diagnosis. They pooled data on more than 77 000 patients from 12 cancer registries and clinics across Europe. Patients were diagnosed between 1940 and 2018, and all‐cause mortality fell steeply during this period. However, excess mortality remained high, even for subjects in their 60s, highlighting the need for long term care for childhood cancer survivors.
Recent studies linking radiation exposure from pediatric computed tomography (CT) to increased risks of leukemia and brain tumors lacked data to control for cancer susceptibility syndromes (CSS). ...These syndromes might be confounders because they are associated with an increased cancer risk and may increase the likelihood of pediatric CT scans. We identify CSS predisposing to leukemia and brain tumors through a systematic literature search and summarize prevalence and risk. Since empirical evidence is lacking in published literature on patterns of CT use for most types of CSS, we estimate confounding bias of relative risks (RR) for categories of radiation exposure based on expert opinion about patterns of CT scans among CSS patients. We estimate that radiation-related RRs for leukemia are not meaningfully confounded by Down syndrome, Noonan syndrome and other CSS. Moreover, tuberous sclerosis complex, von Hippel-Lindau disease, neurofibromatosis type 1 and other CSS do not meaningfully confound RRs for brain tumors. Empirical data on the use of CT scans among CSS patients is urgently needed. Our assessment indicates that associations with radiation exposure from pediatric CT scans and leukemia or brain tumors reported in previous studies are unlikely to be substantially confounded by unmeasured CSS.
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.
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.
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.
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.
•Male childhood cancer survivors have an elevated risk of developing breast cancer.•The absolute risk of male breast cancer in childhood cancer survivors is low.•Risk factors of subsequent male breast cancer remain unclear.•Survivors and their caregivers should be aware of this rare yet serious disease.•Male survivors with breast cancer-related symptoms warrant careful examination.
Pediatric Normal Tissue Effects in the Clinic (PENTEC) is an international multidisciplinary effort that aims to summarize normal-tissue toxicity risks based on published dose-volume data from ...studies of children and adolescents treated with radiation therapy (RT) for cancer. With recognition that children are uniquely vulnerable to treatment-related toxic effects, our mission and challenge was to assemble our group of physicians (radiation and pediatric oncologists, subspecialists), physicists with clinical and modeling expertise, epidemiologists, and other scientists to develop evidence-based radiation dosimetric guidelines, as affected by developmental status and other factors (eg, other cancer therapies and host factors). These quantitative toxicity risk estimates could serve to inform RT planning and thereby improve outcomes. Tandem goals included the description of relevant medical physics issues specific to pediatric RT and the proposal of dose-volume outcome reporting standards to inform future studies. We created 19 organ-specific task forces and methodology to unravel the wealth of data from heterogeneous published studies. This report provides a high-level summary of PENTEC's genesis, methods, key findings, and associated concepts that affected our work and an explanation of how our findings may be interpreted and applied in the clinic. We acknowledge our predecessors in these efforts, and we pay homage to the children whose lives informed us and to future generations who we hope will benefit from this additional step in our path forward.
The relationship between hormone exposure and breast cancer risk in women treated with chest radiotherapy for childhood cancer is uncertain.
Participants included 1108 females from the Childhood ...Cancer Survivor Study who were diagnosed with childhood cancer 1970-1986, treated with chest radiotherapy, and survived to ages ⩾20 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox models adjusted for chest radiation field, delivered dose, anthracycline exposure, and age at childhood cancer estimated risk.
Among 195 women diagnosed with breast cancer, 102 tumours were oestrogen-receptor positive (ER+). Breast cancer risk increased with ⩾10 years of ovarian function after chest radiotherapy vs <10 years (HR=2.89, CI 1.56-5.53) and for radiotherapy given within 1 year of menarche vs >1 year from menarche (HR=1.80, CI 1.19-2.72). Risk decreased with decreasing age at menopause (P
=0.014). Risk factors did not differ for ER+ breast cancer. Survivors with an age at menopause <20 years treated with hormone therapy had a lower breast cancer risk than premenopausal survivors (HR=0.47, CI 0.23-0.94).
Endogenous hormones are key contributors to breast cancer observed among childhood cancer survivors. Hormone therapy given for premature ovarian insufficiency does not fully replace the function that endogenous hormones have in breast cancer development.
Thyroid cancer incidence rates have increased steadily in the United States and elsewhere. Radiation exposure at a young age is a strong risk factor, but otherwise the etiology is unclear. To explore ...etiologic clues, we studied the risk of thyroid cancer after an earlier primary cancer, as well as the risk of developing multiple primaries after an earlier thyroid cancer in the U.S. Surveillance, Epidemiology and End-Results (SEER) cancer registries program (1973-2000). In 2,036,597 patients diagnosed with any invasive cancer who survived for a minimum of 2 months, we observed a 42% increased risk compared to the general population for second thyroid cancer based on 1,366 cases (95% confidence interval (CI) = 35-50%; excess absolute risk (EAR) = 0.38/10,000 person-years (PY)). Elevated risks were observed after most cancer sites studied. The most pronounced excess (observed/expected (O/E) = 2.86) was seen for second thyroid cancers detected in the year after diagnosis of the first cancer. Among 29,456 2-month thyroid cancer survivors, 2,214 second cancers occurred (O/E = 1.11, 95% CI = 1.06-1.15; EAR = 7.64/10,000 PY). Again, the highest risk was seen in the first year (O/E = 1.26). Patients <40 years of age at diagnosis of thyroid cancer had a 39% increased risk of a second cancer, whereas for older patients the risk was elevated 6%. We observed consistently increased risks for cancers of the breast, prostate, and kidney, and a likely radiation treatment-related excess of leukemia. Based on small numbers of cases, cancers of the salivary glands, trachea, scrotum, adrenal glands, and brain and central nervous system (CNS) also occurred in excess. A decreased risk was observed for smoking-related malignancies. Thyroid cancer is associated with primary cancers of many different organs. Although enhanced medical surveillance likely plays a role, 2-way, positive associations between thyroid cancer and cancers of the breast, prostate, kidney, salivary glands, brain and CNS, scrotum, and leukemia suggest etiologic similarities and possible treatment effects.
Abstract
Background
Skin cancer is common after radiotherapy among childhood cancer survivors (CCSs). We studied risks and risk factors for subsequent skin cancers, with emphasis on radiation dose, ...exposed skin surface area, and chemotherapeutic agents.
Methods
The DCOG-LATER cohort study includes 5-year Dutch CCSs diagnosed 1963–2001. Subsequent skin cancers were identified from record linkages with the Netherlands Cancer Registry and Dutch Pathology Registry. Incidence rates were compared with general population rates. Multivariable Cox regression models were used, applying a novel method of case-control sampling enabling use of tumor location in cohort analyses. All statistical tests were two-sided.
Results
Among 5843 CCSs, 259 developed 1061 basal cell carcinomas (BCCs) (standardized incidence ratio SIR = 29.8, 95% confidence interval CI = 26.3 to 33.6; excess absolute risk per 10 000 person-years (EAR) = 24.6), 20 had melanoma (SIR = 2.3, 95% CI = 1.4 to 3.5; EAR = 1.1), and 10 had squamous cell carcinoma (SIR = 7.5, 95% CI = 3.6 to 13.8; EAR = 0.8). Cumulative incidence of BCC 40 years after childhood cancer was 19.1% (95% CI = 16.6 to 21.8%) after radiotherapy vs 0.6% expected based on general population rates. After a first BCC, 46.7% had more BCCs later. BCC risk was associated with any radiotherapy to the skin compartment of interest (hazard ratio HR = 14.32, 95% CI = 10.10 to 20.29) and with estimated percentage in-field skin surface area (26–75%: HR = 1.99, 95% CI = 1.24 to 3.20; 76–100%: HR = 2.16, 95% CI = 1.33 to 3.53, vs 1–25% exposed; Ptrend among exposed = .002), but not with prescribed radiation dose and likelihood of sun-exposed skin-area. Of all chemotherapy groups examined, only vinca alkaloids increased BCC risk (HR = 1.54, 95% CI = 1.04 to 2.27).
Conclusion
CCSs have a strongly, 30-fold increased BCC risk. BCC risk appears to increase with increasing skin surface area exposed. This knowledge underscores the need for awareness by survivors and their health care providers.
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.
Objective
To evaluate trends and patterns in CT usage among children (aged 0–17 years) in The Netherlands during the period 1990–2012.
Methods
Lists of electronically archived paediatric CT scans ...were requested from the Radiology Information Systems (RIS) of Dutch hospitals which reported >10 paediatric CT scans annually in a survey conducted in 2010. Data included patient identification, birth date, gender, scan date and body part scanned. For non-participating hospitals and for years prior to electronic archiving in some participating hospitals, data were imputed by calendar year and hospital type (academic, general with <500 beds, general with ≥ 500 beds).
Results
Based on 236,066 CT scans among 146,368 patients performed between 1990 and 2012, estimated annual numbers of paediatric CT scans in The Netherlands increased from 7,731 in 1990 to 26,023 in 2012. More than 70 % of all scans were of the head and neck. During the last decade, substantial increases of more than 5 % per year were observed in general hospitals with fewer than 500 beds and among children aged 10 years or older.
Conclusion
The estimated number of paediatric CT scans has more than tripled in The Netherlands during the last two decades.
Key Points
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Paediatric CT in The Netherlands has tripled during the last two decades
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The number of paediatric CTs increased through 2012 in general hospitals
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Paediatric CTs continued to increase among children aged 10 years or older
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