Stephanie Lamart

Risk of treatment-related esophageal cancer among breast cancer survivors

BACKGROUND Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use. DESIGN Nested case-control study of esophageal cancer among 289 748 ≥5-year survivors of female breast cancer from five population-based cancer registries (252 cases, 488 individually matched controls), with individualized radiation dosimetry and information abstracted from medical records. RESULTS The largest contributors to esophageal radiation exposure were supraclavicular and internal mammary chain treatments. Esophageal cancer risk increased with increasing radiation dose to the esophageal tumor location (P(trend )< 0.001), with doses of ≥35 Gy associated with an odds ratio (OR) of 8.3 [95% confidence interval (CI) 2.7-28]. Patients with hormonal therapy ≤5 years preceding esophageal cancer diagnosis had lower risk (OR = 0.4, 95% CI 0.2-0.8). Based on few cases, alkylating agent chemotherapy did not appear to affect risk. Our data were consistent with a multiplicative effect of radiation and other esophageal cancer risk factors (e.g. smoking). CONCLUSIONS Esophageal cancer is a radiation dose-related complication of radiotherapy for breast cancer, but absolute risk is low. At higher esophageal doses, the risk warrants consideration in radiotherapy risk assessment and long-term follow-up.

Risk of esophageal cancer following radiotherapy for Hodgkin lymphoma

Advances in Hodgkin lymphoma (HL) treatment have dramatically improved prognosis, with 5-year relative survival now over 80% in the United States (US) and Europe. However, subsequent malignancies, often occurring as late adverse effects of treatment, are a leading cause of morbidity and mortality

COMPARISON OF INTERNAL DOSIMETRY FACTORS FOR THREE CLASSES OF ADULT COMPUTATIONAL PHANTOMS WITH EMPHASIS ON I-131 IN THE THYROID

The 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. The 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 the 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 relatively good agreement between the S values obtained for the ICRP and UF phantoms. Substantial differences were observed for some organs between the three types of phantoms. For example, the small intestine wall of ICRP male phantom and heart wall of ICRP female phantom showed up to eightfold and fourfold 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 the small intestine wall and 3.3-fold greater for the 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 the 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 the SAFs between phantoms in a similar manner as the differences observed in S values but with larger differences at lower photon energies. To investigate the differences observed in the 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.

Computational lymphatic node models in pediatric and adult hybrid phantoms for radiation dosimetry

We developed models of lymphatic nodes for six pediatric and two 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 six 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.

S values for 131I based on the ICRP adult voxel phantoms.

To improve the estimates of organ doses from nuclear medicine procedures using (131)I, the authors calculated a comprehensive set of (131)I S values, defined as absorbed doses in target tissues per unit of nuclear transition in source regions, for different source and target combinations. The authors used the latest reference adult male and female voxel phantoms published by the International Commission on Radiological Protection (ICRP Publication 110) and the (131)I photon and electron spectra from the ICRP Publication 107 to perform Monte Carlo radiation transport calculations using MCNPX2.7 to compute the S values. For each phantom, the authors simulated 55 source regions with an assumed uniform distribution of (131)I. They computed the S values for 42 target tissues directly, without calculating specific absorbed fractions. From these calculations, the authors derived a comprehensive set of S values for (131)I for 55 source regions and 42 target tissues in the ICRP male and female voxel phantoms. Compared with the stylised phantoms from Oak Ridge National Laboratory (ORNL) that consist of 22 source regions and 24 target regions, the new data set includes 1662 additional S values corresponding to additional combinations of source-target tissues that are not available in the stylised phantoms. In a comparison of S values derived from the ICRP and ORNL phantoms, the authors found that the S values to the radiosensitive tissues in the ICRP phantoms were 1.1 (median, female) and 1.3 (median, male) times greater than the values based on the ORNL phantoms. However, for several source-target pairs, the difference was up to 10-fold. The new set of S values can be applied prospectively or retrospectively to the calculation of radiation doses in adults internally exposed to (131)I, including nuclear medicine patients treated for thyroid cancer or hyperthyroidism.

Reconstruction of organ dose for external radiotherapy patients in retrospective epidemiologic studies

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 TPS 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 TPS 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.

Prediction of the location and size of the stomach using patient characteristics for retrospective radiation dose estimation following radiotherapy

Following cancer radiotherapy, reconstruction of doses to organs, other than the target organ, is of interest for retrospective health risk studies. Reliable estimation of doses to organs that may be partially within or fully outside the treatment field requires reliable knowledge of the location and size of the organs, e.g., the stomach, which is at risk from abdominal irradiation. The stomach location and size are known to be highly variable between individuals, but have been little studied. Moreover, for treatments conducted years ago, medical images of patients are usually not available in medical records to locate the stomach. In light of the poor information available to locate the stomach in historical dose reconstructions, the purpose of this work was to investigate the variability of stomach location and size among adult male patients and to develop prediction models for the stomach location and size using predictor variables generally available in medical records of radiotherapy patients treated in the past. To collect data on stomach size and position, we segmented the contours of the stomach and of the skeleton on contemporary computed tomography (CT) images for 30 male patients in supine position. The location and size of the stomach was found to depend on body mass index (BMI), ponderal index (PI), and age. For example, the anteroposterior dimension of the stomach was found to increase with increasing BMI (≈0.25 cm kg(-1) m(2)) whereas its craniocaudal dimension decreased with increasing PI (≈-3.3 cm kg(-1) m(3)) and its transverse dimension increased with increasing PI (≈2.5 cm kg(-1) m(3)). Using the prediction models, we generated three-dimensional computational stomach models from a deformable hybrid phantom for three patients of different BMI. Based on a typical radiotherapy treatment, we simulated radiotherapy treatments on the predicted stomach models and on the CT images of the corresponding patients. Those dose calculations demonstrated good agreement between predicted and actual stomachs compared with doses derived from a reference model of the body that might be used in the absence of individual CT scan data.

Radiation Dose to the Esophagus From Breast Cancer Radiation Therapy, 1943-1996: An International Population-Based Study of 414 Patients

PURPOSE To provide dosimetric data for an epidemiologic study on the risk of second primary esophageal cancer among breast cancer survivors, by reconstructing the radiation dose incidentally delivered to the esophagus of 414 women treated with radiation therapy for breast cancer during 1943-1996 in North America and Europe. METHODS AND MATERIALS We abstracted the radiation therapy treatment parameters from each patients radiation therapy record. Treatment fields included direct chest wall (37% of patients), medial and lateral tangentials (45%), supraclavicular (SCV, 64%), internal mammary (IM, 44%), SCV and IM together (16%), axillary (52%), and breast/chest wall boosts (7%). The beam types used were (60)Co (45% of fields), orthovoltage (33%), megavoltage photons (11%), and electrons (10%). The population median prescribed dose to the target volume ranged from 21 Gy to 40 Gy. We reconstructed the doses over the length of the esophagus using abstracted patient data, water phantom measurements, and a computational model of the human body. RESULTS Fields that treated the SCV and/or IM lymph nodes were used for 85% of the patients and delivered the highest doses within 3 regions of the esophagus: cervical (population median 38 Gy), upper thoracic (32 Gy), and middle thoracic (25 Gy). Other fields (direct chest wall, tangential, and axillary) contributed substantially lower doses (approximately 2 Gy). The cervical to middle thoracic esophagus received the highest dose because of its close proximity to the SCV and IM fields and less overlying tissue in that part of the chest. The location of the SCV field border relative to the midline was one of the most important determinants of the dose to the esophagus. CONCLUSIONS Breast cancer patients in this study received relatively high incidental radiation therapy doses to the esophagus when the SCV and/or IM lymph nodes were treated, whereas direct chest wall, tangentials, and axillary fields contributed lower doses.

Organ Dose Estimates for Hyperthyroid Patients Treated with 131I: An Update of the Thyrotoxicosis Follow-Up Study

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 (131I) treatment (1–4). In the TTFUS cohort, 23,020 patients were treated with 131I, 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 131I treatments per patient was 1.7 ± 1.4 for the GD patients and 2.1 ± 2.1 for the TNG patients. The average total 131I 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 131I to hyperthyroid patients. Based on 131I data for a small, kinetically well-characterized sub-cohort of patients, multivariate regression equations were developed to relate the numbers of disintegrations of 131I 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 131I disintegrations in the organs and tissues of all other hyperthyroid patients in the TTFUS who were treated with 131I. 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 131I for hyperthyroidism.

BODY SIZE-SPECIFIC EFFECTIVE DOSE CONVERSION COEFFICIENTS FOR CT SCANS

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.