Computed tomography (CT), a strong diagnostic tool, delivers higher radiation doses than most imaging modalities. As CT use has increased rapidly, radiation protection is important, particularly ...among children. We evaluate leukemia and brain tumor risk following exposure to low-dose ionizing radiation from CT scans in childhood.
For a nationwide retrospective cohort of 168 394 children who received one or more CT scans in a Dutch hospital between 1979 and 2012 who were younger than age 18 years, we obtained cancer incidence, vital status, and confounder information by record linkage with external registries. Standardized incidence ratios were calculated using cancer incidence rates from the general Dutch population. Excess relative risks (ERRs) per 100 mGy organ dose were calculated with Poisson regression. All statistical tests were two-sided.
Standardized incidence ratios were elevated for all cancer sites. Mean cumulative bone marrow doses were 9.5 mGy at the end of follow-up, and leukemia risk (excluding myelodysplastic syndrome) was not associated with cumulative bone marrow dose (44 cases). Cumulative brain dose was on average 38.5 mGy and was statistically significantly associated with risk for malignant and nonmalignant brain tumors combined (ERR/100 mGy: 0.86, 95% confidence interval = 0.20 to 2.22, P = .002, 84 cases). Excluding tuberous sclerosis complex patients did not substantially change the risk.
We found evidence that CT-related radiation exposure increases brain tumor risk. No association was observed for leukemia. Compared with the general population, incidence of brain tumors was higher in the cohort of children with CT scans, requiring cautious interpretation of the findings.
Background: Ionizing radiation is a well-established human mammary carcinogen. Women historically monitored by radiography
at young ages for abnormal spinal curvature are an exposed population ...suitable for investigating radiation-related risk and
its variation by modifying factors. In this historic cohort, 95% of daily dose increments (when exposure to the breast occurred)
were under 2.4 cGy, with mean 1.1 cGy.
Methods: A retrospective cohort of 3,010 women, diagnosed with spinal curvature between 1912 and 1965 in 14 U.S. pediatric
orthopedic centers and who completed a questionnaire by telephone interview or mail survey in 1992, were studied for risk
of breast cancer by radiation dose to the breast (mean, 12 cGy) after adjustment for established breast cancer risk factors.
Results: A borderline-significant radiation dose response (excess relative risk/Gy = 2.86; P = 0.058; one-tailed P = 0.029) was observed during 118,905 woman-years of follow-up (median, 35.5 years) based on 78 cases of invasive breast cancer.
The dose response was significantly greater ( P = 0.03) for women who reported a family history of breast cancer in first- or second-degree relatives (excess relative risk/Gy
= 8.37; 95% confidence interval, 1.50-28.16). Radiation-related risk did not vary significantly by stage of reproductive development
at exposure.
Conclusions: Assuming that repair of radiation-related DNA damage requires at most a few hours, our data argue against existence
of a low-dose threshold on the order of 1 to 3 cGy for radiation exposure contributing to breast carcinogenesis. The possibility
that a family history of breast cancer may have enhanced a carcinogenic radiation effect requires confirmation in other studies.
(Cancer Epidemiol Biomarkers Prev 2008;17(3):605–13)
Summary Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were given radiation to fields that include breast tissue (ie, chest radiation) have an increased risk of breast ...cancer. Clinical practice guidelines are essential to ensure that these individuals receive optimum care and to reduce the detrimental consequences of cancer treatment; however, surveillance recommendations vary among the existing long-term follow-up guidelines. We applied evidence-based methods to develop international, harmonised recommendations for breast cancer surveillance among female survivors of CAYA cancer who were given chest radiation before age 30 years. The recommendations were formulated by an international, multidisciplinary panel and are graded according to the strength of the underlying evidence.
Purpose Childhood cancer survivors (CCSs) are at increased risk for subsequent malignant neoplasms (SMNs). We evaluated the long-term risk of SMNs in a well-characterized cohort of 5-year CCSs, with ...a particular focus on individual chemotherapeutic agents and solid cancer risk. Methods The Dutch Childhood Cancer Oncology Group-Long-Term Effects After Childhood Cancer cohort includes 6,165 5-year CCSs diagnosed between 1963 and 2001 in the Netherlands. SMNs were identified by linkages with the Netherlands Cancer Registry, the Dutch Pathology Registry, and medical chart review. We calculated standardized incidence ratios, excess absolute risks, and cumulative incidences. Multivariable Cox proportional hazard regression analyses were used to evaluate treatment-associated risks for breast cancer, sarcoma, and all solid cancers. Results After a median follow-up of 20.7 years (range, 5.0 to 49.8 years) since first diagnosis, 291 SMNs were ascertained in 261 CCSs (standardized incidence ratio, 5.2; 95% CI, 4.6 to 5.8; excess absolute risk, 20.3/10,000 person-years). Cumulative SMN incidence at 25 years after first diagnosis was 3.9% (95% CI, 3.4% to 4.6%) and did not change noticeably among CCSs treated in the 1990s compared with those treated earlier. We found dose-dependent doxorubicin-related increased risks of all solid cancers ( P
< .001) and breast cancer ( P
< .001). The doxorubicin-breast cancer dose response was stronger in survivors of Li-Fraumeni syndrome-associated childhood cancers (leukemia, CNS, and non-Ewing sarcoma) versus survivors of other cancers ( P
= .008). In addition, cyclophosphamide was found to increase sarcoma risk in a dose-dependent manner ( P
= .01). Conclusion The results strongly suggest that doxorubicin exposure in CCSs increases the risk of subsequent solid cancers and breast cancer, whereas cyclophosphamide exposure increases the risk of subsequent sarcomas. These results may inform future childhood cancer treatment protocols and SMN surveillance guidelines for CCSs.
Abstract
Background
Breast cancer (BC) risk is increased among Hodgkin lymphoma (HL) survivors treated with chest radiotherapy. Case-control studies showed a linear radiation dose-response ...relationship for estimated dose to the breast tumor location. However, these relative risks cannot be used for absolute risk prediction of BC anywhere in the breasts. Furthermore, the independent and joint effects of radiation dose and irradiated volumes are unclear. Therefore, we examined the effects of mean breast dose and various dose-volume parameters on BC risk in HL patients.
Methods
We conducted a nested case-control study of BC among 5-year HL survivors (173 case patients, 464 matched control patients). Dose-volume histograms were obtained from reconstructed voxel-based 3-dimensional dose distributions. Summary parameters of dose-volume histograms were studied next to mean and median breast dose, Gini index, and the new dose metric mean absolute difference of dose, using categorical and linear excess odds ratio (EOR) models. Interactions between dose-volume parameters and mean dose were also examined.
Results
Statistically significant linear dose-response relationships were observed for mean breast dose (EOR per Gy = 0.19, 95% confidence interval CI = 0.05 to 1.06) and median dose (EOR/Gy = 0.06, 95% CI = 0.02 to 0.19), with no statistically significant curvature. All metrics except Gini and mean absolute difference were positively correlated with each other. These metrics all showed similar patterns of dose-response that were no longer statistically significant when adjusting for mean dose. No statistically significant modification of the effect of mean dose was observed.
Conclusion
Mean breast dose predicts subsequent BC risk in long-term HL survivors.
We studied cancer mortality in a cohort of 5,573 women with scoliosis and other spine disorders who were diagnosed between 1912 and 1965 and were exposed to frequent diagnostic X-ray procedures. ...Patients were identified from medical records in 14 orthopedic medical centers in the United States and followed for vital status and address through December 31, 2004, using publicly available regional, state and nationwide databases. Causes of death were obtained from death certificates or through linkage with the National Death Index (NDI). Statistical analyses included standardized mortality ratios (SMR = observed/expected) based on death rates for U.S. females and internal comparisons using Cox regression models with attained age as the time scale. Diagnostic radiation exposure was estimated from radiology files for over 137,000 procedures; estimated average cumulative radiation doses to the breast, lung, thyroid and bone marrow were 10.9, 4.1, 7.4 and 1.0 cGy, respectively. After a median follow-up period of 47 years, 1527 women died, including 355 from cancer. Cancer mortality was 8% higher than expected (95% CI = 0.97–1.20). Mortality from breast cancer was significantly elevated (SMR = 1.68; 95% CI: 1.38–2.02), whereas death rates from several other cancers were below expectation, in particular lung (SMR = 0.77), cervical (SMR = 0.31), and liver (SMR = 0.17). The excess relative risk (ERR) for breast cancer mortality increased significantly with 10-year lagged radiation dose to the breast (ERR/Gy = 3.9; 95% CI: 1.0–9.3).
Despite the impressive cohort size, analyses by childhood cancer type, subsequent malignant neoplasm type, or specific genes were not feasible, as can be seen from our summary three-way ...classification table of the 28 subsequent malignant neoplasm-related deaths (table).3 Because of the focus on any lethal subsequent malignant neoplasm as an outcome, treatment factors were condensed, and thus nowhere near reflecting the true diversity in radiotherapy characteristics, chemotherapy agents, and hematopoietic stem-cell treatments, nor their effect on specific subsequent malignant neoplasm types.1 Approximately a third of cancer predisposing variant-positive patients with fatal subsequent malignant neoplasms had subsequent malignancies of the CNS (N=9). Analyses of subsequent neoplasm incidence in survivorship cohorts typically show a different distribution and are dominated by more prognostically favourable subsequent cancer types, such as non-melanoma skin cancer, thyroid cancer, breast cancer, and meningioma.1 The authors concluded that testing survivors for highly penetrant cancer predisposing variants holds promise as a risk stratification factor to identify individuals at high risk of subsequent malignant neoplasms. ...a holistic model of care seems needed for childhood cancer survivors positive for cancer predisposing variants, integrating the respective branches of care, thereby uniting the expertise of the cancer predisposition experts with experience from survivorship care teams to ensure adequate attention to all aspects of health.
Although ionizing radiation is an established environmental risk factor for thyroid cancer, the effect of chemotherapy drugs on thyroid cancer risk remains unclear. We evaluated the ...chemotherapy-related risk of thyroid cancer in childhood cancer survivors and the possible joint effects of chemotherapy and radiotherapy.
The study included 12,547 five-year survivors of childhood cancer diagnosed during 1970 through 1986. Chemotherapy and radiotherapy information was obtained from medical records, and radiation dose was estimated to the thyroid gland. Cumulative incidence and relative risks were calculated with life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose.
Histologically confirmed thyroid cancer occurred in 119 patients. Thirty years after the first childhood cancer treatment, the cumulative incidence of thyroid cancer was 1.3% (95% CI, 1.0-1.6) for females and 0.6% (0.4-0.8) for males. Among patients with thyroid radiation doses of 20 Gy or less, treatment with alkylating agents was associated with a significant 2.4-fold increased risk of thyroid cancer (95% CI, 1.3-4.5; P = 0.002). Chemotherapy risks decreased as radiation dose increased, with a significant decrease for patients treated with alkylating agents (P(trend) = 0.03). No chemotherapy-related risk was evident for thyroid radiation doses more than 20 Gy.
Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range less than 20 Gy, in which cell sparing likely predominates over cell killing.
Our study adds to the evidence for chemotherapy agent-specific increased risks of thyroid cancer, which to date, were mainly thought to be related to prior radiotherapy.
As new evidence is available, the International Late Effects of Childhood Cancer Guideline Harmonization Group has updated breast cancer surveillance recommendations for female survivors of ...childhood, adolescent, and young adult cancer.
We used evidence-based methods to apply new knowledge in refining the international harmonized recommendations developed in 2013. The guideline panel updated the systematic literature review, developed evidence summaries, appraised the evidence, and updated recommendations on the basis of evidence, clinical judgement, and consideration of benefits versus the harms of the surveillance interventions while attaining flexibility in implementation across different health care systems. The GRADE Evidence-to-Decision framework was used to translate evidence to recommendations. A survivor information form was developed to counsel survivors about the potential harms and benefits of surveillance.
The literature update identified new study findings related to the effects of prescribed moderate-dose chest radiation (10 to 19 Gy), radiation dose-volume, anthracyclines and alkylating agents in non-chest irradiated survivors, and the effects of ovarian function on breast cancer risk. Moreover, new data from prospective investigations were available regarding the performance metrics of mammography and magnetic resonance imaging among survivors of Hodgkin lymphoma. Modified recommendations include the performance of mammography and breast magnetic resonance imaging for survivors treated with 10 Gy or greater chest radiation (strong recommendation) and upper abdominal radiation exposing breast tissue at a young age (moderate recommendation) at least annually up to age 60 years. As a result of inconsistent evidence, no recommendation could be formulated for routine breast cancer surveillance for survivors treated with any type of anthracyclines in the absence of chest radiation.
The newly identified evidence prompted significant change to the recommendations formulated in 2013 related to moderate-dose chest radiation and anthracycline exposure as well as breast cancer surveillance modality.
From the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative, a systematic review and meta-analysis of publications reporting on radiation dose-volume effects for risk of primary ...hypothyroidism after radiation therapy for pediatric malignancies was performed.
All studies included childhood cancer survivors, diagnosed at age <21 years, whose radiation therapy fields exposed the thyroid gland and who were followed for primary hypothyroidism. Children who received pituitary-hypothalamic or total-body irradiation were excluded. PubMed and the Cochrane Library were searched for studies published from 1970 to 2017. Data on age at treatment, patient sex, radiation dose to neck or thyroid gland, specific endpoints for hypothyroidism that were used in the studies, and reported risks of hypothyroidism were collected. Radiation dose-volume effects were modeled using logistic dose response. Relative excess risk of hypothyroidism as a function of age at treatment and sex was assessed by meta-analysis of reported relative risks (RR) and odds ratios.
Fifteen publications (of 1709 identified) were included for systematic review. Eight studies reported data amenable for dose-response analysis. At mean thyroid doses of 10, 20, and 30 Gy, predicted rates of uncompensated (clinical) hypothyroidism were 4%, 7%, and 13%, respectively. Predicted rates of compensated (subclinical) hypothyroidism were 12%, 25%, and 44% after thyroid doses of 10, 20, and 30 Gy, respectively. Female sex (RR = 1.7, P < .0001) and age >15 years at radiation therapy (RR = 1.3, P = .005) were associated with higher risks of hypothyroidism. After a mean thyroid dose of 20 Gy, predicted risks of hypothyroidism were 13% for males <14 years of age, increasing to 29% for females >15 years of age.
A radiation dose response for risk of hypothyroidism is evident; a threshold radiation dose associated with no risk is not observed. Thyroid dose exposure should be minimized when feasible. Data on hypothyroidism after radiation therapy should be better reported to facilitate pooled analyses.
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