Exposure levels associated with Na(131)I thyroid cancer patients: correlation with initial activity and clinical physical parameters.

Initial radiation exposure levels X (0) at 1 m from the navel of thyroid cancer patients were measured for 165 individuals at the time of ingestion. Some 61 patients had previously signed informed consent so only those patients could be assayed with regard to body parameters. While the activity was in the stomach, resultant X (0) values were seen to be linearly correlated with the total (131)I activity (A) given orally. Yet large differences in X (0) were seen; e.g., at A = 7.4 GBq, variations of a factor of four were found between the largest and smallest exposure rates. Correlation analyses were performed between normalized rate X (0)A-1 and several patient physical parameters. These included age, sex, height, weight, and BMI (body mass index). Only weight and BMI had significant linear correlation (p < 0.05) with normalized exposure rate. In the former case, the correlation coefficient ρ (weight) was -0.296 (p = 0.02). Using BMI as the independent variable, ρ (BMI) was -0.386 (p = 0.0021). With further analysis of the BMI variation, 95% confidence intervals could be determined at various BMI levels. For example, at 28 kg m(-2), the normalized rate varied between 0.039 and 0.0446 µGy h(-1) MBq(-1)-approximately a ±6.5% variation on the mean value of 0.0419 µGy h(-1) MBq(-1) at this BMI. Given such clinical information, differences in normalized exposure rate can be reduced to values on the order of ±10% or less for BMI values over the clinically relevant interval 20 to 40 kg m(-2).

Using a single parameter to describe time-activity curves.

Time-activity uptake curves [u(t) in % injected dose per gram of tissue] may be described by different--often complicated--functional forms. Because of the need to readily compare sequences of engineered radiopharmaceuticals, it is efficient to use mean residence time (MRT) as a one-parameter descriptor. In applying this computation to a sequence of five cognate anti-carcinoembryonic antigen (CEA) antibodies, it was found that the intact form had the longest MRT in the blood with the other four cognates having values less by approximately a factor of 10 or more. This difference probably follows from the lack of an intact Fc segment on the latter engineered molecules. MRT values for a sequence of six scFv-Fc engineered fragments demonstrated that the double mutant had the shortest blood residence time--30-fold less compared with the wild type. Whereas it is not possible to directly apply the MRT to nonbolus (tumor or organ) curves, a residence time (τ) may be assigned using the uptake function. Using τ, it was found that the intact (natural) form of the anti-CEA cognate set had the longest time at the tumor site in the human xenograft model in nude mice. The MRT and τ concept are proposed to also allow comparison of possible relative blood and tissue exposures, respectively, for cognate sets of unlabeled engineered antibodies used to treat malignancies although no data are yet available in the literature for this application.

Review: update on selection of optimal radiopharmaceuticals for clinical trials.

Multiple formulations of radiopharmaceuticals (RPs) are possible because of engineering at the nanometer scale. Yet, numbers of patients are limited, and the cost of each clinical trial is high. Thus, there is the need of preclinical evaluation of one agent versus another for the selection of an optimal choice. In the application of RPs to cancer, this selection involves both visualization and treatment aspects. In this paper, we propose the use of imaging and therapeutic figures of merit (IFOM and TFOM, respectively) to select the optimal structure and radiolabel for subsequent clinical trials given animal biodistribution results. Limiting cases and Monte Carlo simulation were used to demonstrate that these modern figures of merit are superior to traditional ratio functions that have been employed in these two contexts. Finally, there is the question of how animal and human results resemble each other kinetically. We considered allometry and compared mouse and human results for several of the cognate cT84.66 antibodies (anti-CEA; carcinoembryonic antigen). While kinetics of intact and 120-kDa engineered proteins are similar across the two species, the 80-kDa cognate shows a manifest difference in the RP first moment in the blood. In particular, human blood clearance is slower than that seen in the nude mouse. We suggest that such allometric comparisons become standard in the reporting of clinical trials.

The two types of correction of absorbed dose estimates for internal emitters.

BACKGROUND: Two types of correction for absorbed dose (D) estimates are described for clinical applications of internal emitters. The first is appropriate for legal and scientific reasons involving phantom-based estimates; the second is patient-specific and primarily intended for radioimmunotherapy (RIT). METHODS: The Medical Internal Radiation Dose (MIRD) relationship (D) = S A is used, where S is a geometric matrix factor and A is the integral of source organ activities. Internal consistency of the data and the size of organ systems in the humanoid phantom must be assured in both types of estimation. RESULTS: The first dose estimate correction (I) is one whereby computations refer to one or another standard (e.g., MIRD-type) phantom. In this case the S value remains as given, but the measured patient A data must be standardized. The correction factor is the phantom's ratio of organ mass to whole-body mass divided by the same ratio for the volunteer or patient. The second dose estimate correction (II) is patient-specific. While the A value is unchanged for this application, a correction term is provided for the phantom-derived S matrix. The dominant (nonpenetrating radiation) component of this correction factor can be obtained via the ratio of the patient to phantom organ masses. In both corrections, we recommend that true organ sizes, necessary in each method of estimation, be determined in a separate sequence of anatomic images. CONCLUSIONS: In both dose estimation corrections, true sizes of the patient's or volunteer's internal organs must be obtained. Correction due to organ mass size can be severalfold and is probably the dominant uncertainty in the internal emitter absorbed dose calculation process.