Background As cancer survival improves, the long-term risks from treatments including the risk of developing a second cancer after radiotherapy become more important. The proportion of second cancers that may be related to radiotherapy is unknown. Methods We used the U.S. Surveillance, Epidemiology and End Results cancer registries to conduct a systematic analysis of 15 cancer sites that are treated routinely with radiotherapy. Relative risks (RR) for patients receiving radiotherapy versus patients not receiving radiotherapy were estimated using Poisson regression adjusted for age, stage and other potential confounders. Findings The cohort included 647,672 five-year adult survivors followed-up for an average of 7 additional years; 60,271 (9%) developed a second solid cancer. For each of the first cancer sites the RR of developing a second cancer associated with radiotherapy exceeded one, and varied from 1.08 (95%CI:0.79–1.46) after eye/orbit cancers to 1.43 (95%CI:1.13–1.84) after testicular cancer. In general the RR was highest for organs likely to have received >5Gy, decreased with increasing age at diagnosis and increased with time since diagnosis. We estimated a total of 3266 (95%CI:2862–3670) excess second solid cancers that could be related to radiation; 8% (95%CI:7%–9%) of the total in all radiotherapy patients (1+yr survivors) and 5 excess cancers/1,000 patients treated with radiotherapy by 15 years after diagnosis. Approximately half (54%) the excess cancers were in organs likely to have received >5Gy. Interpretation A relatively small proportion of second cancers are related to radiotherapy in adults, suggesting that most are due to other factors, such as lifestyle or genetics.
Organ dose estimation for retrospective epidemiological studies of late effects in radiotherapy patients involves two challenges: radiological images to represent patient anatomy are not usually available for patient cohorts who were treated years ago, and efficient dose reconstruction methods for large-scale patient cohorts are not well established. In the current study, we developed methods to reconstruct organ doses for radiotherapy patients by using a series of computational human phantoms coupled with a commercial treatment planning system (TPS) and a radiotherapy-dedicated Monte Carlo transport code, and performed illustrative dose calculations. First, we developed methods to convert the anatomy and organ contours of the pediatric and adult hybrid computational phantom series to Digital Imaging and Communications in Medicine (DICOM)-image and DICOM-structure files, respectively. The resulting DICOM files were imported to a commercial TPS for simulating radiotherapy and dose calculation for in-field organs. The conversion process was validated by comparing electron densities relative to water and organ volumes between the hybrid phantoms and the DICOM files imported in TPS, which showed agreements within 0.1% and 2%, respectively. Second, we developed a procedure to transfer DICOM-RT files generated from the Eclipse system directly to a Monte Carlo transport code, X-ray Voxel Monte Carlo (XVMC) for more accurate dose calculations. Third, to illustrate the performance of the established methods, we simulated a whole brain treatment for the 10-year-old male phantom and a prostate treatment for the adult male phantom. Radiation doses to selected organs were calculated using the Eclipse and XVMC, and compared to each other. Organ average doses from the two methods matched within 7%, whereas maximum and minimum point doses differed up to 45%. The dosimetry methods and procedures established in this study will be useful for the reconstruction of organ dose to support retrospective epidemiological studies of late effects in radiotherapy patients.
S values for 11 major target organs for I-131 in the thyroid were compared for three classes of adult computational human phantoms: stylized, voxel and hybrid phantoms. In addition, we compared Specific Absorbed Fractions (SAFs) with the thyroid as a source region over a broader photon energy range than the x- and gamma-rays of I-131. S and SAF values were calculated for the International Commission on Radiological Protection (ICRP) reference voxel phantoms and the University of Florida (UF) hybrid phantoms by using Monte Carlo transport method, while the S and SAF values for the Oak Ridge National Laboratory (ORNL) stylized phantoms were obtained from earlier publications. Phantoms in our calculations were for adults of both genders. The 11 target organs and tissues that were selected for the comparison of S values are: brain, breast, stomach wall, small intestine wall, colon wall, heart wall, pancreas, salivary glands, thyroid, lungs, and active marrow for I-131 and thyroid as a source region. The comparisons showed, in general, an underestimation of S values reported for the stylized phantoms compared to the values based on the ICRP voxel and UF hybrid phantoms and a relatively good agreement between the S values obtained for the ICRP and UF phantoms. Substantial differences were observed for some organs between the 3 types of phantoms. For example, the small intestine wall of ICRP male phantom and heart wall of ICRP female phantom showed up to 8-fold and 4-fold greater S values, respectively, compared to the reported values for the ORNL phantoms. UF male and female phantoms also showed significant differences compared to the ORNL phantom, 4.0-fold greater for small intestine wall and 3.3-fold greater for heart wall. In our method, we directly calculated the S values without using the SAFs as commonly done. Hence, we sought to confirm the differences observed in our S values by comparing SAFs among the phantoms with the thyroid as a source region for selected target organs - small intestine wall, lungs, pancreas and breast as well as illustrate differences in energy deposition across the energy range (12 photon energies from 0.01 to 4 MeV). Differences were found in SAFs between phantoms in a similar manner to the differences observed in S values but with larger differences at lower photon energies. To investigate the differences observed in S and SAF values, the chord length distributions (CLDs) were computed for the selected source-target pairs and compared across the phantoms. As demonstrated by the CLDs, we found that the differences between phantoms in those factors used in internal dosimetry were governed to a significant degree by inter-organ distances which are a function of organ shape as well as organ location.
We developed models of lymphatic nodes for 6 pediatric and 2 adult hybrid computational phantoms to calculate the lymphatic node dose estimates from external and internal radiation exposures. We derived the number of lymphatic nodes from the recommendations in International Commission on Radiological Protection (ICRP) Publications 23 and 89 at 16 cluster locations for the lymphatic nodes: extrathoracic, cervical, thoracic (upper and lower), breast (left and right), mesentery (left and right), axillary (left and right), cubital (left and right), inguinal (left and right), and popliteal (left and right), for different ages (newborn, 1-, 5-, 10-, 15-year-old, and adult). We modeled each lymphatic node within the voxel format of the hybrid phantoms by assuming that all nodes have identical size derived from published data except narrow cluster sites. The lymph nodes were generated by the following algorithm: (1) selection of the lymph node site among the 16 cluster sites; (2) random sampling of the location of the lymph node within a spherical space centered at the chosen cluster site; (3) creation of the sphere or ovoid of tissue representing the node based on lymphatic node characteristics defined in ICRP Publications 23 and 89. We created lymph nodes until the pre-defined number of lymphatic nodes at the selected cluster site was reached. This algorithm was applied to pediatric (newborn, 1-, 5-, and 10-year-old male, and 15-year-old males) and adult male and female ICRP-compliant hybrid phantoms after voxelization. To assess the performance of our models for internal dosimetry, we calculated dose conversion coefficients, called S values, for selected organs and tissues with Iodine-131 distributed in 6 lymphatic node cluster sites using MCNPX2.6, a well validated Monte Carlo radiation transport code. Our analysis of the calculations indicates that the S values were significantly affected by the location of the lymph node clusters and that the values increased for smaller phantoms due to the shorter inter-organ distances compared to the bigger phantoms. By testing sensitivity of S values to random sampling and voxel resolution, we confirmed that the lymph node model is reasonably stable and consistent for different random samplings and voxel resolutions.
Effective dose from computed tomography (CT) examinations is usually estimated using the scanner-provided dose-length product and using conversion factors, also known as k-factors, which correspond to scan regions and differ by age according to five categories: 0, 1, 5, 10 y and adult. However, patients often deviate from the standard body size on which the conversion factor is based. In this study, a method for deriving body size-specific k-factors is presented, which can be determined from a simple regression curve based on patient diameter at the centre of the scan range. Using the International Commission on Radiological Protection reference paediatric and adult computational phantoms paired with Monte Carlo simulation of CT X-ray beams, the authors derived a regression-based k-factor model for the following CT scan types: head-neck, head, neck, chest, abdomen, pelvis, abdomen-pelvis (AP) and chest-abdomen-pelvis (CAP). The resulting regression functions were applied to a total of 105 paediatric and 279 adult CT scans randomly sampled from patients who underwent chest, AP and CAP scans at the National Institutes of Health Clinical Center. The authors have calculated and compared the effective doses derived from the conventional age-specific k-factors with the values computed using their body size-specific k-factor. They found that by using the age-specific k-factor, paediatric patients tend to have underestimates (up to 3-fold) of effective dose, while underweight and overweight adult patients tend to have underestimates (up to 2.6-fold) and overestimates (up to 4.6-fold) of effective dose, respectively, compared with the effective dose determined from their body size-dependent factors. The authors present these size-specific k-factors as an alternative to the existing age-specific factors. The body size-specific k-factor will assess effective dose more precisely and on a more individual level than the conventional age-specific k-factors and, hence, improve awareness of the true exposure, which is important for the clinical community to understand.
The Thyrotoxicosis Therapy Follow-up Study (TTFUS) is comprised of 35,593 hyperthyroid patients treated from the mid-1940s through the mid-1960s. One objective of the TTFUS was to evaluate the long-term effects of high-dose iodine-131 ((131)I) treatment (1-4). In the TTFUS cohort, 23,020 patients were treated with (131)I, including 21,536 patients with Graves disease (GD), 1,203 patients with toxic nodular goiter (TNG) and 281 patients with unknown disease. The study population constituted the largest group of hyperthyroid patients ever examined in a single health risk study. The average number (± 1 standard deviation) of (131)I treatments per patient was 1.7 ± 1.4 for the GD patients and 2.1 ± 2.1 for the TNG patients. The average total (131)I administered activity was 380 ± 360 MBq for GD patients and 640 ± 550 MBq for TNG patients. In this work, a biokinetic model for iodine was developed to derive organ residence times and to reconstruct the radiation-absorbed doses to the thyroid gland and to other organs resulting from administration of (131)I to hyperthyroid patients. Based on (131)I data for a small, kinetically well-characterized sub-cohort of patients, multivariate regression equations were developed to relate the numbers of disintegrations of (131)I in more than 50 organs and tissues to anatomical (thyroid mass) and clinical (percentage thyroid uptake and pulse rate) parameters. These equations were then applied to estimate the numbers of (131)I disintegrations in the organs and tissues of all other hyperthyroid patients in the TTFUS who were treated with (131)I. The reference voxel phantoms adopted by the International Commission on Radiological Protection (ICRP) were then used to calculate the absorbed doses in more than 20 organs and tissues of the body. As expected, the absorbed doses were found to be highest in the thyroid (arithmetic means of 120 and 140 Gy for GD and TNG patients, respectively). Absorbed doses in organs other than the thyroid were much smaller, with arithmetic means of 1.6 Gy, 1.5 Gy and 0.65 Gy for esophagus, thymus and salivary glands, respectively. The arithmetic mean doses to all other organs and tissues were more than 100 times less than those to the thyroid gland. To our knowledge, this work represents the most comprehensive study to date of the doses received by persons treated with (131)I for hyperthyroidism.
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