Bone Marrow Radiation Dose Research Articles

Image-guided radiation therapy for functional bone marrow sparing in patients with pelvic malignancies.

e13570 Background: Hematologic toxicity (HT) is a significant problem in patients undergoing chemoradiotherapy (CRT) for pelvic malignancies. We tested the hypothesis that image-guided radiation therapy (IGRT) could reduce functional bone marrow (FBM) radiation dose, potentially reducing HT. Methods: We enrolled 10 patients with cervix (n=5) or anal (n=5) cancer onto a prospective IRB-approved protocol. Patients underwent CT simulation plus (1) whole body 18F-FDG-PET/CT and (2) quantitative MRI using iterative decomposition of water and fat with echo asymmetry and least-squares estimation (MRI-IDEAL). Regions of high standardized uptake value (SUV) (increased glucose metabolism) on PET and low fat fraction (high cellularity) on MRI-IDEAL indicated higher FBM concentrations. The PET/CT and MRI-IDEAL were registered with the simulation CT, and FBM was automatically segmented based on the mean SUV and fat fraction within the pelvic bone. For each patient, 4 plans were compared: intensity modulated radiation ...

Impact of Bone Marrow Radiation Dose on Acute Hematologic Toxicity in Cervical Cancer: Principal Component Analysis on High Dimensional Data

To study the effects of increasing pelvic bone marrow (BM) radiation dose on acute hematologic toxicity in patients undergoing chemoradiotherapy, using a novel modeling approach to preserve the local spatial dose information. The study included 37 cervical cancer patients treated with concurrent weekly cisplatin and pelvic radiation therapy. The white blood cell count nadir during treatment was used as the indicator for acute hematologic toxicity. Pelvic BM radiation dose distributions were standardized across patients by registering the pelvic BM volumes to a common template, followed by dose remapping using deformable image registration, resulting in a dose array. Principal component (PC) analysis was applied to the dose array, and the significant eigenvectors were identified by linear regression on the PCs. The coefficients for PC regression and significant eigenvectors were represented in three dimensions to identify critical BM subregions where dose accumulation is associated with hematologic toxicity. We identified five PCs associated with acute hematologic toxicity. PC analysis regression modeling explained a high proportion of the variation in acute hematologicity (adjusted R(2), 0.49). Three-dimensional rendering of a linear combination of the significant eigenvectors revealed patterns consistent with anatomical distributions of hematopoietically active BM. We have developed a novel approach that preserves spatial dose information to model effects of radiation dose on toxicity, which may be useful in optimizing radiation techniques to avoid critical subregions of normal tissues. Further validation of this approach in a large cohort is ongoing.

Whole pelvic helical tomotherapy for locally advanced cervical cancer: technical implementation of IMRT with helical tomotherapy.

BackgroundTo review the experience and to evaluate the treatment plan of using helical tomotherapy (HT) for the treatment of cervical cancer.MethodsBetween November 1st, 2006 and May 31, 2009, 10 cervical cancer patients histologically confirmed were enrolled. All of the patients received definitive concurrent chemoradiation (CCRT) with whole pelvic HT (WPHT) followed by brachytherapy. During WPHT, all patients were treated with cisplatin, 40 mg/m2 intravenously weekly. Toxicity of treatment was scored according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0).ResultsThe mean survival was 25 months (range, 3 to 27 months). The actuarial overall survival, disease-free survival, locoregional control and distant metastasis-free rates at 2 years were 67%, 77%, 90% and 88%, respectively. The average of uniformity index and conformal index was 1.06 and 1.19, respectively. One grade 3 of acute toxicity for diarrhea, thrombocytopenia and three grade 3 leucopenia were noted during CCRT. Only one grade 3 of subacute toxicity for thrombocytopenia was noted. There were no grade 3 or 4 subacute toxicities of anemia, leucopenia, genitourinary or gastrointestinal effects. Compared with conventional whole pelvic radiation therapy (WPRT), WPHT decreases the mean dose to rectum, bladder and intestines successfully.ConclusionHT provides feasible clinical outcomes in locally advanced cervical cancer patients. Long-term follow-up and enroll more locally advanced cervical carcinoma patients by limiting bone marrow radiation dose with WPHT technique is warranted.

Dosimetry of 90Y-Ibritumomab Tiuxetan as Consolidation of First Remission in Advanced-Stage Follicular Lymphoma: Results from the International Phase 3 First-Line Indolent Trial

The objective of this analysis was to assess the radiation exposure associated with (90)Y-ibritumomab tiuxetan when used as consolidation therapy in adults with low or minimal tumor burden after first-line therapy of advanced follicular lymphoma (FL). The patients who were enrolled in the phase 3 first-line indolent trial were 18 y or older, with CD20(+) grade 1 or 2 stage III or IV FL, and a partial response, complete response, or unconfirmed complete response to first-line chemotherapy. The patients were allocated randomly to receive a single infusion of unlabeled rituximab 250 mg/m(2) on day -7 and consolidation on day 0 with a single dose of (90)Y-ibritumomab tiuxetan, 14.8 MBq/kg, immediately after unlabeled rituximab, 250 mg/m(2), or no further treatment. On day -7, a subset of patients received an injection of 185 MBq of (111)In-ibritumomab tiuxetan immediately after unlabeled rituximab, 250 mg/m(2), for central dosimetry analysis. Correlations were assessed between organ radiation absorbed dose and toxicity, body weight, body mass index, and progression-free survival. Central dosimetry evaluations were available from 57 of 70 patients. Median radiation absorbed doses were 100 cGy (range, 28-327 cGy) for the red marrow and 72 cGy (range, 46-106 cGy) for the whole body. Radiation absorbed doses did not differ significantly between patients who had a partial response or complete response to initial therapy. Progression-free survival correlated significantly with the whole-body (r = 0.4401; P = 0.0006) and bone marrow (r = 0.2976; P = 0.0246) radiation dose. Body weight was significantly negatively correlated with whole-body radiation dose (r = -0.4971; P < 0.0001). Neither the whole-body radiation dose nor the bone marrow radiation dose correlated with hematologic toxicity. In patients with low or minimal residual tumor burden after first-line chemotherapy of advanced FL, whole-body and bone marrow exposure after (90)Y-ibritumomab tiuxetan consolidation showed a significant positive correlation with progression-free survival, whereas dosimetric data could not predict hematologic toxicity.

Modeling Effects of 3D Pelvic Bone Marrow Radiation Dose on Acute Hematologic Toxicity using Principal Components Analysis

Current normal tissue complication (NTCP) models of radiation effects on bone marrow (BM) are limited without considering the spatial radiation dose distribution. Our goal was to develop a model that incorporates spatial dose distributions, to help identify BM subregions where dose accumulation is important for predicting hematologic toxicity (HT), and to guide optimization of BM-sparing radiation techniques.

Leukemia: lessons from the Japanese experience.

Probably more has been learned about radiation-induced leukemia from intensive study of Japanese atomic bomb survivors than about radiation damage to any other organ system. This has been the result of an intensive binational effort at the Atomic Bomb Casualty Commission and the Radiation Effects Research Foundation in Hiroshima and Nagasaki to monitor the occurrence of leukemia in a large group of atomic bomb survivors over a period of more than 50 years (the Life Span Study). The focus in the leukemia studies has been on disease latency, time of peak incidence rates, clinical course, shape of the dose-response curve and changes in risk over time for various types of leukemia in relationship to shielded kerma and bone marrow radiation dose, age at time of exposure, and gender. The extreme understanding and cooperation of the Japanese atomic bomb survivors, control subjects, physicians of Hiroshima and Nagasaki, government authorities, and the citizens of both cities has resulted in an epidemiological study that is almost unparalleled in medical history.

WE‐E‐BRD‐01: Investigating Effects of Pelvic Bone Marrow Radiation Dose On Acute Hematologic Toxicity Using High Dimensional Data Analysis

Purpose: To develop a new method to investigate the effect of local pelvic bone marrow (BM) radiation dose on acute hematologic toxicity (HT) in cervical cancer patients undergoing concurrent chemoradiation therapy (CRT), with the ultimate goal of optimizing BM‐sparing radiation techniques. Method and Materials: We analyzed 24 cervical cancer patients treated with concurrent cisplatin (40mg/m2/week) and pelvic IMRT. The white blood cell count (WBC) nadir, defined as the lowest value occurring between the start of CRT and two weeks following IMRT, was used as the indicator of acute HT. The pelvic bone region included the os coxae, lower lumbar vertebrae, sacrum, acetabulae, and proximal femora. BM doses were standardized in two steps: pelvic bone registration followed by dose remapping. Simulation CT images were registered to a common (canonical) template using the optical flow based deformable image registration developed by Yang et al.[2]. The deformation field was used to remap the dose distribution back to the deformed pelvic bones. We generated a data structure called a “dose‐array” that reserves the spatial information of each dose value. The position of an element inside array can be used to trace its location in 3D. Results: Substantial variation of BM dose distribution among the 24 patients was observed. Patients were classified based on their WBC nadir value (⩾ vs. &lt; 2000/μL) into two groups (n=15 vs. n=9, respectively), and the average pelvic BM 3‐D dose distribution was compared visually. Results suggested that patients receiving higher doses to the lower lumbar spine, upper sacrum, and medial ilium, were more likely to develop acute HT. Conclusion: We have developed a novel method to study the impact of BM radiation dose on acute HT. Our next step is to implement both unsupervised and supervised classification models to analyze radiation effects, for use in IMRT plan optimization.

The Ukrainian-American Study of Leukemia and Related Disorders among Chornobyl Cleanup Workers from Ukraine: III. Radiation Risks

Leukemia is one of the cancers most susceptible to induction by ionizing radiation, but the effects of lower doses delivered over time have not been quantified adequately. After the Chornobyl (Chernobyl) accident in Ukraine in April 1986, several hundred thousand workers who were involved in cleaning up the site and its surroundings received fractionated exposure, primarily from external gamma radiation. To increase our understanding of the role of protracted low-dose radiation exposure in the etiology of leukemia, we conducted a nested case-control study of leukemia in a cohort of cleanup workers identified from the Chornobyl State Registry of Ukraine. The analysis is based on 71 cases of histologically confirmed leukemia diagnosed in 1986-2000 and 501 age- and residence-matched controls selected from the same cohort. Study subjects or their proxies were interviewed about their cleanup activities and other relevant factors. Individual bone marrow radiation doses were estimated by the RADRUE dose reconstruction method (mean dose = 76.4 mGy, SD = 213.4). We used conditional logistic regression to estimate leukemia risks. The excess relative risk (ERR) of total leukemia was 3.44 per Gy [95% confidence interval (CI) 0.47-9.78, P < 0.01]. The dose response was linear and did not differ significantly by calendar period of first work in the 30-km Chornobyl zone, duration or type of work. We found a similar dose-response relationship for chronic and non-chronic lymphocytic leukemia [ERR = 4.09 per Gy (95% CI < 0-14.41) and 2.73 per Gy (95% CI < 0-13.50), respectively]. To further clarify these issues, we are extending the case-control study to ascertain cases for another 6 years (2001-2006).

Increased Frequency of Chromosome Translocations Associated with Diagnostic X-Ray Examinations

Informative studies of cancer risks associated with medical radiation are difficult to conduct owing to low radiation doses, poor recall of diagnostic X rays, and long intervals before cancers occur. Chromosome aberrations have been associated with increased cancer risk and translocations are a known radiation biomarker. Seventy-nine U.S. radiologic technologists were selected for blood collection, and translocations were enumerated by whole chromosome painting. We developed a dose score to the red bone marrow for medical radiation exposure from X-ray examinations reported by the technologists that they received as patients. Using Poisson regression, we analyzed translocations in relation to the dose scores. Each dose score unit approximated 1 mGy. The estimated mean cumulative red bone marrow radiation dose score was 42 (range 1-265). After adjustment for age, occupational radiation, and radiotherapy for benign conditions, translocation frequencies significantly increased with increasing red bone marrow dose score with an estimate of 0.007 translocations per 100 CEs per score unit (95% CI, 0.002 to 0.013; P = 0.01). Chromosome damage has been linked with elevated cancer risk, and we found that cumulative radiation exposure from medical X-ray examinations was associated with increased numbers of chromosome translocations.

High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases.

Samarium-153 ethylene diamine tetramethylene phosphonate ((153)Sm-EDTMP), a bone-seeking radiopharmaceutical, provides therapeutic irradiation to osteoblastic bone metastases. Because the dose-limiting toxicity of (153)Sm-EDTMP is thrombocytopenia, a dose-escalation trial using peripheral-blood progenitor cells (PBPCs) or marrow support was conducted to treat metastatic bone cancer. Patients with locally recurrent or metastatic osteosarcoma or skeletal metastases avid on bone scan were treated with 1, 3, 4.5, 6, 12, 19, or 30 mCi/kg of (153)Sm-EDTMP. Thirty patients were treated with (153)Sm-EDTMP. Transient symptoms of hypocalcemia were seen at 30 mCi/kg. Estimates of radioisotope bound to bone surfaces and marrow radiation dose were linear with injected amount of (153)Sm-EDTMP. Cytopenias also occurred in all subjects and were dose-related. At day +13 after (153)Sm-EDTMP, residual whole-body radioactivity was 1% to 65% of whole-body radioactivity considered safe for PBPC infusion, 3.6 mCi. After PBPC or marrow infusion on day +14 after (153)Sm-EDTMP, recovery of hematopoiesis was problematic in two patients at the 30 mCi/kg dose infused with less than 2 x 10(6) CD34(+)/kg on day +14, but not in other patients. Reduction or elimination of opiates for pain was seen in all patients. Patients had no adverse changes in appetite or performance status. (153)Sm-EDTMP with PBPC support can provide bone-specific therapeutic irradiation (estimates of 39 to 241 Gy). Hematologic toxicity at 30 mCi (153)Sm-EDTMP/kg requires PBPC grafts with more than 2 x 10(6) CD34(+)/kg to overcome myeloablative effects of skeletal irradiation. Nonhematologic side effects are minimal.

High-Dose Samarium-153 Ethylene Diamine Tetramethylene Phosphonate: Low Toxicity of Skeletal Irradiation in Patients With Osteosarcoma and Bone Metastases

PURPOSE: Samarium-153 ethylene diamine tetramethylene phosphonate (153Sm-EDTMP), a bone-seeking radiopharmaceutical, provides therapeutic irradiation to osteoblastic bone metastases. Because the dose-limiting toxicity of 153Sm-EDTMP is thrombocytopenia, a dose-escalation trial using peripheral-blood progenitor cells (PBPCs) or marrow support was conducted to treat metastatic bone cancer. PATIENTS AND METHODS: Patients with locally recurrent or metastatic osteosarcoma or skeletal metastases avid on bone scan were treated with 1, 3, 4.5, 6, 12, 19, or 30 mCi/kg of 153Sm-EDTMP. RESULTS: Thirty patients were treated with 153Sm-EDTMP. Transient symptoms of hypocalcemia were seen at 30 mCi/kg. Estimates of radioisotope bound to bone surfaces and marrow radiation dose were linear with injected amount of 153Sm-EDTMP. Cytopenias also occurred in all subjects and were dose-related. At day +13 after 153Sm-EDTMP, residual whole-body radioactivity was 1% to 65% of whole-body radioactivity considered safe for PBPC infu...

Biodistribution of 111In- and 90Y-labeled DOTA and maleimidocysteineamido-DOTA conjugated to chimeric anticarcinoembryonic antigen antibody in xenograft-bearing nude mice: comparison of stable and chemically labile linker systems.

Biodistributions of two radiometal chelate conjugates of the human/murine chimeric anticarcinoembryonic antigen monoclonal antibody cT84.66 were obtained in nude mice bearing LS174T human colorectal carcinoma xenografts. Derivatives of the macrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) were covalently attached to the antibody by a stable amide linkage and by a maleimidocysteineamido side chain (MC-DOTA) that has been shown to be chemically labile at physiological temperature and pH. Biodistributions of both 111In and 90Y labels were obtained in these studies. At common biodistribution time points, it was found that the 111In label had greater uptake in the liver than 90Y for both conjugates. No significant differences were found with respect to bone uptake of 90Y using either chelate. Blood curves were generally lower at comparable time points for MC-DOTA, indicative of faster clearance as compared to DOTA. Tumor uptake was high for both conjugates (57-68% ID/g at 48 h), with a longer tumor residence time in the case of the DOTA conjugate, probably a result of its longer blood circulation times. We conclude that bone uptake of 90Y would be minimal if either DOTA or MC-DOTA were used as the bifunctional chelator. This would imply preference for these macrocyclic ligands if radiation doses to the bone marrow would be considered to be dominated by skeletal uptakes. Alternatively, if bone marrow radiation dose is dominated by circulating antibody, the chemically labile linker system employed by the MC-DOTA conjugate offers the advantage of enhanced blood clearance.

1223 - Relationship between rate of “in-field” bone marrow regeneration and radiation dose in patients with Hodgkin's disease

1223 - Relationship between rate of “in-field” bone marrow regeneration and radiation dose in patients with Hodgkin's disease

Potential contribution of 131I-Labelled monoclonal anti-CEA antibodies in the treatment of liver metastases from colorectal carcinomas: Pretherapeutic study with dose recovery in resected tissues

20 patients with liver metastases from colorectal carcinoma undergoing laparotomy received 15-60 mg intravenously, either intact or fragments of, anti-carcinoembryonic antigen (anti-CEA) monoclonal antibodies labelled with 0.55-1.48 GBq (15-40 mCi) of 131I, 3-8 days prior to operation. The uptake measured per gram of metastases ranged from 0.33 to 6.6 x 10(-3%) of injected dose. Tumour to liver uptake ratios ranged from 2 to 33. The radiation dose, estimated in 6 patients (3 of each group), for an extrapolated dose of 3.7 GBq (100 mCi) of 131I ranged from 0.3 to 0.8 Gy in normal liver or spleen (an acceptable estimate for bone marrow radiation dose) and from 3.4 to 8.2 Gy to the hepatic metastases, indicating that probably other therapeutic modalities should be associated with radioimmunotherapy.

Study of the clinical thermoluminescent dosimeter in the direct measurement of radiation absorbed dose for radioimmunotherapy

One of the major obstacles facing radioimmunotherapy (RIT) is the lack of a device to measure directly tumor and normal tissue radiation absorbed dose. Calculations based on the clearance and imaging scans have several limitations; hence we design and fabricate a sheathed clinical thermoluminescent dosimeter (TLD) for the measurement of absorbed dose by implantation in humans. Preclinical studies are performed in nine normal rabbits. Complete blood count, body temperature monitoring, clinical observation and necropsy show no untoward effects from the TLD. Consistent bone marrow radiation doses are noted in the four rabbits receiving 131I-labeled monoclonal antibody A6H. By using up to 20 clinical TLDs in one sheath, it will be possible to determine macroscopic heterogeneities in organs undergoing RIT.

A technique for measuring regional bone mineral density in human lumbar vertebral bodies.

A method for measuring the regional bone mineral density (rBMD) in human lumbar vertebral bodies using a series of contiguous computed tomography images, each 1 mm thick, is fully described. The technique has a sample volume of 0.004 cm3, a sample spacing of 0.8 X 0.8 X 1.0 mm, and results in a bone marrow radiation dose of 1.59 to 2.75 rads (0.016-0.028 Gy). The use of physical density (mg/cm3) is introduced and the measurement noise (0.7-1.3%), accuracy (2.7%), and serial precision (0.2%) have been evaluated in vitro using appropriate phantoms. The corresponding percentage errors for accuracy and precision relative to K2HPO4 concentration were 6.9% and 2.0%, respectively. A multiple region density measurement is described and evaluated.