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.

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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.