Biomedical subjects

Hazel Breitz

Publications and source records attributed to Hazel Breitz.

8 recordsLinked to original sources

PubMed2005

Testicular uptake and radiation dose in patients receiving Zevalin and Pretarget CC49Fusion protein.

OBJECTIVE: Radiation dose to the testes from radionuclide therapies is of concern. This study evaluated image-quantification methods for testicular uptake in a phantom and in patients. METHODS: A 50-mL vial and a large water tank were used to simulate testes and the body, respectively. Activity concentration in the vial and water tank was prepared to generate testes-to-background concentrations of 1.3 and 1.1. Five male lymphoma patients who received a Zevalin (Biogen Idec, Cambridge, MA) regimen and 6 male colorectal cancer patients who received a Pretarget (Neo Rx, Seattle, WA) CC49Fusion protein were evaluated. Testicular activity was quantified using two methods: (1) geometric-mean, background-corrected testicular region of interest (ROI) counts as a fraction of body counts without explicit attenuation correction (Zevalin Kit); (2) background-corrected anterior testicular ROI counts with attenuation correction using known depth in the phantom and CT depth in patients. RESULTS: In the phantom study, Method 1 underestimated 49% and 39%, at image contrast of 1.3 and 1.1, respectively. Quantification was improved using Method 2 (7% for a 1.3 contrast, -17% for a 1.1 contrast). Method 2 was used in patients because background-corrected posterior ROI counts were statistically unreliable due to poor image contrast. In patients receiving Zevalin, the median peak percent injected dose (%ID)/testis was 0.10 (range, 0.08-0.18) with a median biologic half-time (T(bio1/2)) of 156 (range, 91-4200) hours. The median dose was 2.4 (range, 1.5-3.6) Gy/GBq, compared to the originally reported mean dose of 9.1 (range, 5.4-11.4) Gy/GBq (Zevalin package insert). In patients receiving the Pretarget CC49Fusion protein, the median peak %ID/testis was 0.22 (range, 0.05-0.29) with a median T(bio1/2) of 44 (range, 37-64) hours. The median dose was 0.84 (range, 0.3-1.2) Gy/GBq. CONCLUSION: This study found that testicular doses from Zevalin were much lower than that originally reported in the package insert. The median testicular dose from Pretarget CC49Fusion protein was less than half that of the median testicular dose from Zevalin.

Antibodies, Monoclonal↗

PubMed2005

Pretargeted radioimmunotherapy (RIT) with a novel anti-TAG-72 fusion protein.

Pretargeted radioimmunotherapy (RIT) increases the dose of radionuclide delivered to tumor sites while limiting radiation to normal tissues. The three components in Pretarget include a streptavidin-containing targeting molecule, a synthetic clearing agent (sCA), and (90)Y and/or (111)In-DOTA-biotin. This trial determined the feasibility and safety of using a genetically engineered fusion protein directed to TAG-72 as the targeting agent. Nine (9) patients with metastatic colorectal cancer (TAG-72+) received 160 mg/m(2) of CC49Fusion protein intravenously (i.v.), followed by the sCA, 45 mg/m(2) i.v. Twenty-four (24) hours later, patients received radiolabeled DOTA-biotin (either 0.65 or 1.3 mg/m(2)). All patients received 5 mCi of (111)In-DOTA-biotin for imaging and dosimetry purposes and patients 4-9 received 10 mCi/m2 of (90)Y-DOTA-biotin as well. The mean plasma T1/2 of CC49Fusion protein was 23 +/- 6 hours. Greater than 95% of the circulating CC49Fusion protein was eliminated from the circulation within 6 hours of sCA administration. The radiolabeled DOTA-biotin rapidly localized to tumor sites while the unbound fraction was rapidly excreted. The mean tumor-to-marrow radiation dose ratio was 139:1 and mean tumor: whole body was 56:1. No infusion-related, renal, hepatic, or hematologic toxicities were noted. CC49Fusion protein performs well in a pretargeted RIT schema, and further study with escalating doses of (90)Y should be pursued. This strategy has the potential to deliver effective radiation tumor doses to TAG- 72+ tumors.

Adenocarcinoma↗

PubMed2005

Patient-specific dosimetry of pretargeted radioimmunotherapy using CC49 fusion protein in patients with gastrointestinal malignancies.

UNLABELLED: Pretargeted radioimmunotherapy (RIT) using CC49 fusion protein, comprised of CC49-(scFv)4 and streptavidin, in conjunction with 90Y/111In-DOTA-biotin (DOTA = dodecanetetraacetic acid) provides a new opportunity to improve efficacy by increasing the tumor-to-normal tissue dose ratio. To our knowledge, the patient-specific dosimetry of pretargeted 90Y/111In-DOTA-biotin after CC49 fusion protein in patients has not been reported previously. METHODS: Nine patients received 3-step pretargeted RIT: (a) 160 mg/m2 of CC49 fusion protein, (b) synthetic clearing agent (sCA) at 48 or 72 h later, and (c) 90Y/111In-DOTA-biotin 24 h after the sCA administration. Sequential whole-body 111In images were acquired immediately and at 2-144 h after injection of 90Y/111In-DOTA-biotin. Geometric-mean quantification with background and attenuation correction was used for liver and lung dosimetry. Effective point source quantification was used for spleen, kidneys, and tumors. Organ and tumor 90Y doses were calculated based on 111In imaging data and the MIRD formalism using patient-specific organ masses determined from CT images. Patient-specific marrow doses were determined based on radioactivity concentration in the blood. RESULTS: The 90Y/111In-DOTA-biotin had a rapid plasma clearance, which was biphasic with <10% residual at 8 h. Organ masses ranged from 1,263 to 3,855 g for liver, 95 to 1,009 g for spleen, and 309 to 578 g for kidneys. The patient-specific mean 90Y dose (cGy/37 MBq, or rad/mCi) was 0.53 (0.32-0.78) to whole body, 3.75 (0.63-6.89) to liver, 2.32 (0.58-4.46) to spleen, 7.02 (3.36-11.2) to kidneys, 0.30 (0.09-0.44) to lungs, 0.22 (0.12-0.34) to marrow, and 28.9 (4.18-121.6) to tumors. CONCLUSION: Radiation dose to normal organs from circulating radionuclide is substantially reduced using pretargeted RIT. Tumor-to-normal organ dose ratios were increased about 8- to 11-fold compared with reported patient-specific mean dose to liver, spleen, marrow, and tumors from 90Y-CC49.

Aged↗

PubMed2004

Dosimetry model for radioactivity localized to intestinal mucosa.

BACKGROUND: This paper provides a new model for calculating radiation-absorbed doses to the full thickness of the small and large intestinal walls, and to the mucosal layers. The model was used to estimate the intestinal radiation doses from yttrium-90-labeled-DOTA-biotin binding to NR-LU-10-streptavidin in patients. METHODS: We selected model parameters from published data and observations, and used the model to calculate energy-absorbed fractions using the EGS4 radiation transport code. We determined the cumulated (90)Y activity in the small and large intestines of patients from gamma camera images, and calculated absorbed doses to the mucosal layer and to the whole intestinal wall. RESULTS: The mean absorbed dose to the wall of the small intestine was 16.2 mGy/MBq (60 cGy/mCi) administered from (90)Y localized in the mucosa, and 70 mGy/MBq (260 cGy/mCi) to the mucosal layer within the wall. Doses to the large intestinal wall and to the mucosa of the large intestine were lower than those for the small intestine by a factor of about 2.5. These doses are greater by factors of about 5 to 6 than those that would have been calculated using the standard MIRD models that assume the intestinal activity is in the bowel contents. CONCLUSIONS: The specific uptake of radiopharmaceuticals in mucosal tissues may lead to dose-related intestinal toxicities. Tissue dosimetry at the sub-organ level is useful for a better understanding of intestinal tract radiotoxicity and associated dose-response relationships.

Humans↗

PubMed2004

Clinical aspects of radiation nephropathy.

Small radiolabeled molecules are finding increasing clinical use for targeted radionuclide therapy. With the administration of radiolabeled small molecules, the bone marrow is not necessarily the first organ to show radiation toxicity. Rapid excretion of radioactivity through the urinary tract and the retention of radiolabeled small-protein molecules in the kidneys may expose the kidneys to radiation sufficient enough to cause toxicity--and in clinical trials, radiation toxicity of the urinary tract has become clinically relevant. The cells of the kidneys are slowly repairing cells; thus, the radiation toxicity may not be manifest for several months. The clinical and pathological features associated with radiation nephropathy, and issues particular to radiation nephropathy following targeted radionuclide therapy, are described here.

Animals↗

PubMed2003

166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials.

Holmium-166 1, 4, 7, 10-tetraazcyclododecane-1, 4, 7, 10-tetramethylenephosphonate (166Ho-DOTMP) is a radiotherapeutic that localizes specifically to the skeleton and can deliver high-dose radiation to the bone and bone marrow. In patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation two phase 1/2 dose-escalation studies of high-dose 166Ho-DOTMP plus melphalan were conducted. Patients received a 30 mCi (1.110 Gbq) tracer dose of 166Ho-DOTMP to assess skeletal uptake and to calculate a patient-specific therapeutic dose to deliver a nominal radiation dose of 20, 30, or 40 Gy to the bone marrow. A total of 83 patients received a therapeutic dose of 166Ho-DOTMP followed by autologous hematopoietic stem cell transplantation 6 to 10 days later. Of the patients, 81 had rapid and sustained hematologic recovery, and 2 died from infection before day 60. No grades 3 to 4 nonhematologic toxicities were reported within the first 60 days. There were 27 patients who experienced grades 2 to 3 hemorrhagic cystitis, only 1 of whom had received continuous bladder irrigation. There were 7 patients who experienced complications considered to be caused by severe thrombotic microangiopathy (TMA). No cases of severe TMA were reported in patients receiving in 166Ho-DOMTP doses lower than 30 Gy. Approximately 30% of patients experienced grades 2 to 4 renal toxicity, usually at doses targeting more than 40 Gy to the bone marrow. Complete remission was achieved in 29 (35%) of evaluable patients. With a minimum follow-up of 23 months, the median survival had not been reached and the median event-free survival was 22 months. 166Ho-DOTMP is a promising therapy for patients with multiple myeloma and merits further evaluation.

Adult↗

PubMed2003

Dosimetry of high dose skeletal targeted radiotherapy (STR) with 166Ho-DOTMP.

A study was undertaken to determine the maximum tolerated dose of (166)Ho-DOTMP that could be administered safely, without negatively impacting marrow re-engraftment, in patients with multiple myeloma treated with melphalan prior to transplant. Ho-166 DOTMP is a tetraphosphonate that localizes rapidly to bone surface. The Ho-166 physical half-life is 26.8 hr and the maximum beta energy is 1.8 MeV. Standard dosimetry models were adapted for radiation absorbed dose estimates using data obtained from whole body counting of the low abundance photons emitted by (166)Ho. Eighty-three patients received high dose (166)Ho-DOTMP followed by melphalan and transplant of peripheral blood stem cells. Twenty-five patients also received 8 Gy total body radiation (TBI). Dosages administered ranged from 460 to 4476 mCi (166)Ho-DOTMP. Marrow dose was derived using the assumption that all radioactivity not excreted by 20 hours was localized to the bone surfaces, and applying the Eckerman bone and marrow dose model to the calculated bone residence times. The dosimetry of the urinary bladder and kidneys was important because of the rapid excretion of the non-targeted radioactivity via the urinary pathway. The dynamic bladder model was used for bladder wall surface dose, and the ICRP 53 kinetic model was used to model kidney kinetics with an additional blood component included. Marrow doses ranged from 13 to 59 Gy and successful hematapoietic recovery occurred. Bladder doses ranged from 4.7 to 157 Gy. Hemorrhagic cystitis occurred in some patients who received more than 40 Gy to the bladder wall surface. Bladder irrigation was successful in protecting patients from bladder toxicity. Kidney doses ranged from 0.5-7.9 Gy. Kidney toxicity in the form of thrombotic microangiopathy with renal dysfunction was observed, with the severity being related to Ho-166-DOTMP radiation dose and probably the dose rate as well. In a future trial, kidney dosimetry will be assessed using early serial gamma camera imaging and modifications will be implemented to reduce renal toxicity.

Antineoplastic Agents, Alkylating↗

PubMed2002

Dosimetry in a myeloablative setting.

In clinical therapy trials using high dosages of systemically administered radioactivity to treat cancer, myeloablation may occur. This is either an effect of the circulating radioactivity labeled to antibodies exposing the bone marrow to radiation, or it may occur because malignant cells in the bone marrow are targeted. Bone marrow cells may be targeted through antigens expressed on cells in the bone marrow or because radioactivity is targeted to the skeleton. Assessment of radiation absorbed dose to the marrow may be useful for dose escalation or individualized patient treatment planning. With successful preservation of marrow function with autologous marrow or peripheral blood stem cell transplantation, other normal organs may also receive sufficient radiation to show toxicity. Accurate dose estimates to these organs is important for the design of future studies in order to minimize or avoid toxicity. This paper reviews internally administered high dose radiation therapy studies, and examines the radiation absorbed dose estimates reported from these studies.

Animals↗