Indium-111 satumomab pendetide: the first FDA-approved monoclonal antibody for tumor imaging

OBJECTIVE: Colon cancer is the second most common cause of cancer mortality. Ovarian cancer is the most common gynecologic malignancy cause of death in women. A labeled monoclonal antibody attaches to a tumor-associated antigen and allows these tumor masses to be imaged or treated, depending on the radionuclide used. Indium-111 satumomab pendetide was the first labeled monoclonal antibody to be approved by the Food and Drug Administration (FDA) for tumor imaging. It is reactive with most colorectal and ovarian cancers, as well as other cancers. After reading this article, the technologist will understand the FDA approval process, phase trial results, safety and adverse reactions, human antimurine antibody response, indications, imaging protocol, and strengths and weaknesses of imaging with satumomab pendetide. Representative cases are presented.     

Ultrasonic absorbed dose, dose rate, and produced lesion volume

Histological preparations of ultrasonically produced lesions in cat brain, at 3 and 4 MHz, have been studied microscopically. The relationship of the delivered acoustic intensity at the lesion site, the energy absorbed per unit volume of the lesion, and the lesion volume is exhibited. It is suggested that universal responses to ultrasonic exposure may exist for different tissues.     

Conversion of ionization measurements to radiation absorbed dose in non-water density material

The radiation absorbed dose to non-water equivalent materials of interest in radiotherapy is the dose to lung and the dose to bone. The measurement and calculation of dose to the lung has been of great interest and much effort has gone into the development of accurate lung dose calculation methods. The radiation absorbed dose to the bone is usually not calculated and most absorbed dose calculations have been done without correcting for the presence of bone. For the lower megavoltage photon beams this may be appropriate, however, as the energy of the photon beam increases, the region of electronic disequilibrium becomes larger and pair production which depends on the atomic number of the material becomes significant. Therefore the bone will produce greater perturbations of the dose distribution. The dose to lung-equivalent material is uniquely obtained from ionization measurements. However, in bone-equivalent materials two different calculations of absorbed dose are possible: the absorbed dose to soft tissue plastic (polystyrene) within bone-equivalent material and the dose to the bone-equivalent material itself. Both can be calculated from ionization measurements in phantoms. These two calculations result in significantly different doses in a heterogeneous phantom composed of polystyrene and aluminium (a bone substitute). The dose to a thin slab of polystyrene in aluminium is much higher than the dose to the aluminium itself at the same depth in the aluminium. Monte Carlo calculations confirm that the calculation of dose to polystyrene in aluminium can be accurately carried out using existing dosimetry protocols. However, the conversion of ionization measurements to absorbed dose to high atomic number materials cannot be accurately carried out with existing protocols and appropriate conversion factors need to be determined.     

Marrow toxicity and radiation absorbed dose estimates from rhenium-186-labeled monoclonal antibody

Estimates of radiation absorbed dose to the red marrow (RM) would be valuable in treatment planning for radioimmunotherapy if they could show a correlation with clinical toxicity. In this study, a correlation analysis was performed to determine whether estimates of radiation absorbed dose to the bone marrow could accurately predict marrow toxicity in patients who had received 186Re-labeled monoclonal antibody. METHODS: White blood cell and platelet count data from 25 patients who received 186Re-NR-LU-10 during Phase I radioimmunotherapy trials were analyzed, and the toxicity grade, the fraction of the baseline counts at the nadir (percentage baseline) and the actual nadir were used as the indicators of marrow toxicity. Toxicity was correlated with various predictors of toxicity. These predictors included the absorbed dose to RM, the absorbed dose to whole body (WB) and the total radioactivity administered. RESULTS: Percentage baseline and grade of white blood cells and platelets all showed a moderate correlation with absorbed dose and radioactivity administered (normalized for body size). The percentage baseline platelet count was the indicator of toxicity that achieved the highest correlation with the various predictors of toxicity (r = 0.73-0.79). The estimated RM absorbed dose was not a better predictor of toxicity than either the WB dose or the total radioactivity administered. There was substantial variation in the blood count response of the patients who were administered similar radioactivity doses and who had similar absorbed dose estimates. CONCLUSION: Although there was a moderately good correlation of toxicity with dose, the value of the dose estimates in predicting toxicity is limited by the patient-to-patient variability in response to internally administered radioactivity. In this analysis of patients receiving 186Re-labeled monoclonal antibody, a moderate correlation of toxicity with dose was observed but marrow dose was of limited use in predicting toxicity for individual patients.     

Importance of pre-treatment radiation absorbed dose estimation for radioimmunotherapy of non-Hodgkin''s lymphoma

We have been developing a new type of centrifugal pump for long-term use. The magnetically suspended centrifugal pump (MSCP) contains no shaft and seal so that long life expectancy is predicted. Paracorporeal left ventricular (LV) assist circulation between the left atrium and the descending aorta was instituted using sheep. The flow rates ranged from 2.5-5.5 L/min. The sheep that lived the longest (46 days) died of an embolism as a result of the thrombus in the pump. No thrombus formation was observed in other pumps. Plasma free hemoglobin levels ranged from 9 to 18 mg/dl, which led to the conclusion that the hemolysis level remained within an acceptable range. Two driving modes were compared. The slope of the pressure-flow relationship plot under a constant motor current mode was steeper than that under a constant rotational speed mode, and thus, the flow fluctuation decreased. In conclusion, the MSCP is durable for more than a month at the current stage of development and is a promising device for long-term ventricular assist.     

Expression of manganese superoxide dismutase reduces tumor control radiation dose: gene-radiotherapy

This study investigated the in vitro and in vivo radiation response of tumor cells transfected with human manganese superoxide dismutase (MnSOD) cDNA. A major objective was to test the potential tumor suppressive effect of MnSOD in vivo. Tumor cells studied were an in vitro line derived from a murine spontaneous fibrosarcoma, FSa-II, which expressed an undetectable MnSOD activity. These cells were transfected with pSV2-NEO plasmid (NEO line) or cotransfected with MnSOD plasmid plus pSV2-NEO plasmid (SOD lines) as described previously. The cell lines used were SOD-L and SOD-H, which expressed, respectively, low and high MnSOD activities after transfection, and NEO and parental FSa-II controls. Both SOD-L and SOD-H cell lines were slightly more resistant to ionizing radiation than were the two control cell lines when irradiated in vitro in the presence of oxygen. The dose-modifying factors calculated at the survival level of 0.01 were 1.13 and 1.15 for the SOD-L and SOD-H cells, respectively. To investigate potential tumor suppressive effects, animal tumors of 4 mm diameter were irradiated in vivo under hypoxic conditions, and the radiation dose to control one-half of the irradiated tumors (TCD50) was determined for each tumor. The TCD50S obtained on the basis of the tumor control rate in 120 days after irradiation were substantially lower for the SOD-H and SOD-L tumors compared to the NEO tumors. They were 22.9, 28.6, and 47.5 Gy for SOD-H, SOD-L and NEO tumors, respectively. To analyze these data, survival curves were obtained for hypoxic cells by irradiating NEO and SOD-H tumors under hypoxic conditions in vivo and assaying in vitro. Analysis of these curves suggests that the decrease in the TCD50S of SOD tumors is attributable to the reduced tumorigenicity in these tumors. The hypoxic cell survival curves also showed that SOD did not protect cells from radiation in the absence of oxygen. Electron microscopy showed no morphological differences between these cells. These results suggest that the fraction of tumorigenic cells could be reduced by expression of MnSOD, resulting in a substantial decrease in the TCD50.     

Pharmacokinetic modeling and absorbed dose estimation for chimeric anti-CEA antibody in humans

The objective of this article was to model pharmacokinetic data from clinical diagnostic studies involving the 111In-labeled monoclonal antibody (MAb) chimeric T84.66, against carcinoembryonic antigen. Model-derived results based on the 111In-MAb blood, urine and digital imaging data were used to predict 90Y-MAb absorbed radiation doses and to guide treatment planning for future therapy trials. Fifteen patients with at least one carcinoembryonic antigen-positive lesion were evaluated. We report the kinetic parameter estimates and absorbed 111In-MAb dose and projected 90Y-MAb doses for each patient as well as describe our approach and rationale for modeling an extensive set of pharmacokinetic data. METHODS: The ADAPT II software package was used to create three- and five-compartment models of uptake against time in the patient population. The "best-fit" model was identified using ordinary least squares. Areas under the curve were calculated using the modeled curves and input into MIRDOSE3 to estimate absorbed radiation doses for each patient. RESULTS: A five-compartment model best described the liver, whole body, blood and urine data for a subcohort of nine patients with digital imaging data. A three-compartment model best described the blood and urine data for all 15 clinical patients accrued in the clinical trial. For the subcohort, the largest projected 90Y-MAb doses were delivered to the liver (mean, 24.78 rad/mCi; range, 15.02-37.07 rad/mCi), with red marrow estimates on the order of 3.32 rad/mCi (range, 1.24-5.55) of 90Y. Corresponding estimates for the 111In-MAb were 3.18 (range, 2.09-4.43) and 0.55 (range, 0.34-0.74), respectively. CONCLUSION: The three- and five-compartment models presented here were successfully used to represent the blood, urine and imaging data. This was evidenced by the small standard errors for the kinetic parameter estimates and R2 values close to 1. As planned future therapeutic trials will involve stem cell support to alleviate hematological toxicities, the development of an approach for estimating doses to other major organs is crucial.     

Digital radiography in paediatrics: radiation dose considerations and magnitude of possible dose reduction

The purpose of this study was to evaluate the radiation doses received by paediatric patients examined using a digital radiography unit, and to compare these doses with those received from conventional screen-film systems. In this way, guidelines could be drawn up concerning the magnitude of possible dose reductions achievable using digital radiography. The study was undertaken on approximately 900 patients undergoing abdomen, chest, pelvis and skull examinations. Patients were categorized into the following age groups: 0-1 month, 1-12 months, 1-5 years, 5-10 years and 10-15 years. Approximately half were X-rayed using a Fuji computed radiography system and half using a conventional screen-film system. Entrance surface dose was calculated from the recorded exposure parameters and measured X-ray tube outputs. Dose-area product was recorded directly. Image quality was assessed clinically using criteria recommended by a working group of the Commission of the European Communities. Apart from chest examinations, it was found possible to reduce doses by about 40% on average, by using a computed radiography system instead of a 600 speed screen-film combination. There was no significant difference in the dose for chest examinations. Satisfactory image quality can therefore be achieved by using computed radiography as a 1000 speed system for abdomen, pelvis and skull examinations, and as a 600 speed system for chests. Since very few departments appear to use screen-film systems of speeds greater than 400, then, for most departments, the use of computed radiography would result in dose reductions of at least 60%, or 33% for chests.     

Evaluation of external radiation exposure rate from radioiodine-treated hyperthyroid patients and radiation safety considerations

Hyperthyroid patients treated with radioiodine (131I) pose an external radiation risk to individuals who come into close contact with them. In order to determine changes in levels of external radiation with time in relation to the dose administered, 38 hyperthyroid patients being treated with 131I were evaluated Thyroid uptake, plasma T3, T4 and TSH levels were measured prior to treatment. Using a Geiger-Muller probe, levels of external radiation were measured at distances of 0.3, 0.6, 1.0 and 2.0 m from the patient -at the level at which the maximum activity was recorded -30 min, 1, 3, 7 and 10 days post-therapy. The patients were split into two groups. Group I comprised 22 patients treated with < or = 370 MBq 131I, 5 (23%) of whom registered > 0.46 mC kg-1 at a distance of 1.0 m 30 min post-therapy. Group II comprised 16 patients treated with > 370 MBq 131I, 13 (81%) of whom registered 0.46 mC kg-1 at a distance of 1.0 m one day post-therapy. At 3 days in Group I and 7 days in Group II, the estimated total radiation exposure rates were found to exceed the 1994 US Nuclear Regulatory Commission dose limits for children and pregnant women. Based on the results obtained, we present some guidelines intended to prevent the public from unnecessary radiation exposures.     

The dose absorbed by lymphocytes irradiated in vitro with tritiated water

A simple method of irradiating cells in vitro with beta particles is to add the beta-emitter to a cell suspension; various dosimetric aspects of this procedure have been investigated. It is shown that, due to the different water content of the various constituents of a blood cell suspension, the average dose D beta absorbed by a certain type of cells for a tritium nominal concentration Co and an irradiation time t is given by D beta(t) = KEnCo eta t. Typical values of the factor eta are calculated for lymphocytes. A series of experiments has demonstrated that whilst the uptake phase has negligible effect on the dose, a significant error may arise during washing-out because a proportion of the activity remains in the cells.     

Comparison of high dose rate, low dose rate, and high dose rate fractionated radiation for optimizing differences in radiosensitivities in vitro

In an attempt to clarify the biological nature of a human endogenous retrovirus (HERV), HERV-R, which is a single-copy type of HERVs and is conserved as a full-length viral sequence, the expression of HERV-R mRNA in normal autopsied systemic organs was examined by Northern blot analysis. The expression showed different levels among individuals, with the adrenal glands expressing the highest level of HERV-R among all organs tested, except for the placenta. In various adrenal tumors, HERV-R was expressed at high levels in all cortical adenomas but less so in pheochromocytomas. In situ hybridization revealed the expression of HERV-R to be localized in all layers of the adrenal cortex, but not in the medulla. This high-level expression of HERV-R in the adrenal cortex may possibly relate to differentiation and/or steroid production by adrenocortical cells.     

Bispecific monoclonal antibody-mediated targeting of an indium-111-labeled DTPA dimer to primary colorectal tumors: pharmacokinetics, biodistribution, scintigraphy and immune response

Eleven patients with primary colorectal carcinoma tumors (4 +/- 2 cm) were given intravenous injections of 1-10 mg of an anti-CEA, anti-In-DTPA bispecific Fab'-Fab monoclonal antibody, and 2-8 days later, were injected with 1.2-4.2 nmol of an 111In-labeled DTPA dimer (6 mCi). The bispecific antibody exhibited good stability and F(ab)'2-like pharmacokinetics. After injection, the 111In-DTPA dimer distributed in a large volume (88 ml/kg-180 ml/kg) and cleared through the kidneys (mean residence time in the whole body: 9 hr-16 hr). Uptake of 111In by the tumor using this two-step technique (1.8%-17.5% injected dose ID/kg, measured from surgical samples 48 hr after hapten injection) was not found significantly lower than that achieved with our reference 111In-labeled anti-CEA F(ab)'2 1 to 4 days after injection in six patients with similar clinical status (5.5%-30.2% ID/kg). In addition, tumor-to-blood and tumor-to-liver uptake ratios were significantly improved (blood 7.8 versus 4.2, liver 2.8 versus 0.8). As a result, low background images allowed detection of 12 of 13 lesions, 4 hr and 24 hr after hapten injection. However, 7 of 11 patients developed HAMA.     

Estimation of radiation absorbed doses to the red marrow in radioimmunotherapy

Myelotoxicity is the dose-limiting factor in radioimmunotherapy. Traditional methods most commonly used to estimate the radiation adsorbed dose to the bone marrow of patients consider contributions from radionuclide in the blood and/or total body. Targeted therapies, such as radioimmunotherapy, add a third potential source for radiation to the bone marrow because the radiolabeled targeting molecules can accumulate specifically on malignant target cells infiltrating the bone marrow. A non-invasive method for estimating the radiation absorbed dose to the red marrow of patients who have received radiolabeled monoclonal antibodies (MoAb) has been developed and explored. The method depends on determining the cumulated activity in three contributing sources: 1) marrow; 2) blood; and 3) total body. The novel aspect of this method for estimating marrow radiation dose is derivation of the radiation dose for the entire red marrow from radiation dose estimates obtained by detection of cumulated activity in three lumbar vertebrae using a gamma camera. Contributions to the marrow radiation dose from marrow, blood, and total body cumulated activity were determined for patients who received an I-131 labeled MoAb, Lym-1, that reacts with malignant B-lymphocytes of chronic lymphocytic leukemia and nonHodgkin's lymphoma. Six patients were selected for illustrative purposes because their vertebrae were readily visualized on lumbar images. The radiation doses to the marrow contributed by nonpenetrating emissions in the marrow blood and penetrating emissions in the total body were similar in these patients with a mean of 0.2 and 0.3 rads per administered mCi from the blood and total body, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Indium-111 pentetreotide single-photon emission tomography in patients with TSH-secreting pituitary adenomas: correlation with the effect of a single administration of octreotide on serum TSH levels

Few data are available on the visualization of somatostatin receptors in vivo in patients with thyrotropin (TSH)-secreting adenoma. We studied five patients with TSH-secreting adenomas using single-photon emission tomography (SPET) after administration of indium-111 pentetreotide. The intensity of 111In-pentetreotide uptake by the tumours was correlated with the degree of TSH suppression after a single administration of 100 microg octreotide s. c. Five patients (three women and two men) aged 27-46 years were investigated. Except for one patient with acromegaly, all had pure TSH-secreting tumours. One patient was previously untreated, while two had received octreotide, one antithyroid drugs, and one radioiodine. In all patients SPET demonstrated increased uptake of 111In-pentetreotide by the pituitary adenoma. The target to non-target ratio (T/nT) of 111In-pentetreotide uptake was higher than 10 in three patients. Administration of 100 microg octreotide s. c. caused a significant reduction in TSH levels from 4.8+/-1.4 mU/l to a nadir of 3.1+/-1.1 mU/l after 6 h (P<0.001 by ANOVA). Suppression of TSH secretion ranged from 30% to 60% of the baseline value. The T/nT ratio showed a trend toward a direct relationship with the degree of TSH inhibition after acute octreotide administration (r=0.67; P=NS). Our study showed that 111In-pentetreotide scan visualized somatostatin receptors in all five of the patients with TSH-secreting pituitary adenomas, confirming the frequent presence of somatostatin receptors in these rare tumours, even though the correlation with the TSH inhibition after a single administration of octreotide did not reach significance.     

Patient and staff radiation dose in fluoroscopy-guided TIPS procedures and dose reduction, using dedicated fluoroscopy exposure settings

Fluoroscopy guided interventions, such as transjugular intrahepatic portosystemic shunt (TIPS) procedures, can results in relatively high radiation doses to patients and staff. The purpose of this study was to evaluate the possible benefit of dedicated fluoroscopy exposure factors in the reduction of doses. Doses to patients and staff were measured during fluoroscopy-guided TIPS procedures in two Dutch university hospitals. Patient doses were calculated from dose-area product (DAP) measurements, entrance beam dimensions and DAP conversion factors. Staff doses were measured outside lead aprons using electronic personal dosemeters. Average patient entrance skin dose (ESD) rate during fluoroscopy was 49 mGy min-1 (13 cases, average fluoroscopy duration 32 min) in one hospital, and 6 mGy min-1 (10 cases, average fluoroscopy duration 50 min) in the other. Estimated staff effective dose per procedure was 28 microSv average in the first hospital compared with 4 microSv average in the other. The use of dedicated fluoroscopy exposure factors, with a relatively high tube voltage and lower tube current resulted in a significant dose reduction for patient and staff in this type of radiological intervention.     

Mercury exposure from dental amalgam fillings: absorbed dose and the potential for adverse health effects

This review examines the question of whether adverse health effects are attributable to amalgam-derived mercury. The issue of absorbed dose of mercury from amalgam is addressed first. The use of intra-oral Hg vapor measurements to estimate daily uptake must take into account the differences between the collection volume and flow rate of the measuring instrument and the inspiratory volume and flow rate of air through the mouth during inhalation of a single breath. Failure to account for these differences will result in substantial overestimation of the absorbed dose. Other factors that must be considered when making estimates of Hg uptake from amalgam include the accurate measurement of baseline (unstimulated) mercury release rates and the greater stimulation of Hg release afforded by chewing gum relative to ordinary food. The measured levels of amalgam-derived mercury in brain, blood, and urine are shown to be consistent with low absorbed doses (1-3 micrograms/day). Published relationships between the number of amalgam surfaces and urine levels are used to estimate the number of amalgam surfaces that would be required to produce the 30 micrograms/g creatinine urine mercury level stated by WHO to be associated with the most subtle, pre-clinical effects in the most sensitive individuals. From 450 to 530 amalgam surfaces would be required to produce the 30 micrograms/g creatinine urine mercury level for people without any excessive gum-chewing habits. The potential for adverse health effects and for improvement in health following amalgam removal is also addressed. Finally, the issue of whether any material can ever be completely exonerated of claims of producing adverse health effects is considered.