BACKGROUND Two types of correction for absorbed dose (D̄) 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 (D̄) = S à is used, where S is a geometric matrix factor and à 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 à 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 à 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. Cancer 2002;94:1231–4. © 2002 American Cancer Society. DOI 10.1002/cncr.10290
Multiple formulations of radiopharmaceuticals (RPs)
Intrapatient variation in the biodistribution of the chimeric monoclonal antibody cT84.66 was assessed in 19 patients having a variety of carcinoembryonic antigen (CEA) positive tumors. The two studies, including whole-body imaging and blood and urine specimen collections, were conducted within 14 days of each other using (111)In-cT84.66 at a fixed total protein dose of 5 mg per patient per study. An initial pretherapy infusion of (111)In-cT84.66 was administered followed by a therapy coinfusion of (111)In-ct84.66 and 90Y-cT84.66 A closed five-compartment model was used to integrate source organ activity curves as residence time inputs into the MIRDOSE3 program. Normal organ absorbed doses were estimated for 90Y-cT84.66, the corresponding radiotherapeutic agent. For the two (111)In-cT84.66 biodistributions, all data were modeled with a R2 value of between 0.72 and 1.00 with the exception of the urine data taken during therapy. This was due to the need of diethylenetriaminepentaacetic acid during the therapy phase because of the possibility that yttrium might escape from the chelator attached to the antibody. With the assurance that the biodistributions were reproducible, we were able to estimate the 90Y-cT84.66 absorbed doses on a per-patient basis. Concordance coefficients showing the agreement between the imaging and therapy phase dose estimates were between the 0.60 and 0.99 levels for liver, spleen, red marrow, total body, and other organ systems. Median results were: 27, 17, and 2.7 rad/mCi of 90Y-cT84.66 for liver, spleen, and red marrow, respectively. Because of decreases in platelets and white cells as the amount of 90Y was increased, dose-limiting toxicity was found at 22 mCi/m2. We conclude that patient biodistributions were consistent over time to 14 days so as to allow absorbed dose estimation in a radioimmunotherapy trial involving the cT84.66 anti-CEA antibody.
Targeting of monoclonal antibody (Mab) to solid tumor sites is a function of the blood curve of activity versus time. It has been suggested that the blood curve be artificially reduced to approach zero so that the contrast between tumor and blood uptake is maximized. We analyzed tumor uptake as a function of the time tc of blood curve truncation. By using a convolution approach, we were able to find the optimal times for setting the blood curve to zero in either diagnostic or therapeutic animal examples. Two iodinated cT84.66 anti-CEA engineered fragments, diabody and minibody, were considered using previous data from nude mouse studies involving the LS174T colorectal tumor model. Figures of merit (FOMs) were used to compare ordinary and truncated blood curves and their associated tumor accumulations. Using a 1231 label, it was seen that the appropriate time for diagnostic truncation occurred when tumor uptake, as measured, was a maximum. The corresponding point for therapy (with 1311 as a label) was at infinite time. We also demonstrated that the use of traditional indices led to ambiguities in the choice of truncation times. The traditional therapy index, the ratio of the integral of the tumor uptake to the integral of the blood uptake, was found to be a numerical constant independent of tc. This ratio was proved to be the integral of the tumor impulse response function. Use of such convolution techniques to assess truncation of the perfused material is probably also applicable to multistep processes as well as to lesion targeting with other tumor-specific pharmaceuticals.
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.
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