Barry W. Wessels

MIRD Pamphlet No. 21: A Generalized Schema for Radiopharmaceutical Dosimetry—Standardization of Nomenclature

The internal dosimetry schema of the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine has provided a broad framework for assessment of the absorbed dose to whole organs, tissue subregions, voxelized tissue structures, and individual cellular compartments for use in both diagnostic and therapeutic nuclear medicine. The schema was originally published in 1968, revised in 1976, and republished in didactic form with comprehensive examples as the MIRD primer in 1988 and 1991. The International Commission on Radiological Protection (ICRP) is an organization that also supplies dosimetric models and technical data, for use in providing recommendations for limits on ionizing radiation exposure to workers and members of the general public. The ICRP has developed a dosimetry schema similar to that of the MIRD Committee but has used different terminology and symbols for fundamental quantities such as the absorbed fraction, specific absorbed fraction, and various dose coefficients. The MIRD Committee objectives for this pamphlet are 3-fold: to restate its schema for assessment of absorbed dose in a manner consistent with the needs of both the nuclear medicine and the radiation protection communities, with the goal of standardizing nomenclature; to formally adopt the dosimetry quantities equivalent dose and effective dose for use in comparative evaluations of potential risks of radiation-induced stochastic effects to patients after nuclear medicine procedures; and to discuss the need to identify dosimetry quantities based on absorbed dose that address deterministic effects relevant to targeted radionuclide therapy.

MIRD Pamphlet No. 22 (Abridged): Radiobiology and Dosimetry of α-Particle Emitters for Targeted Radionuclide Therapy

The potential of α-particle emitters to treat cancer has been recognized since the early 1900s. Advances in the targeted delivery of radionuclides and radionuclide conjugation chemistry, and the increased availability of α-emitters appropriate for clinical use, have recently led to patient trials of radiopharmaceuticals labeled with α-particle emitters. Although α-emitters have been studied for many decades, their current use in humans for targeted therapy is an important milestone. The objective of this work is to review those aspects of the field that are pertinent to targeted α-particle emitter therapy and to provide guidance and recommendations for human α-particle emitter dosimetry.

Overview of animal studies comparing radioimmunotherapy with dose equivalent external beam irradiation

As the field of radioimmunotherapy (RIT) continues to develop and looks increasingly promising, there is growing interest in the radiobiology of RIT. Recently, several investigators have conducted studies in animal models comparing the relative efficacy of RIT with dose equivalent external beam irradiation. Although these studies are the first of many to follow, the results are provocative and several patterns are suggested by the available data. The results of the studies are summarized and compared, and preliminary hypotheses that might explain the reported observations are discussed. In summary, results from studies comparing the efficacy of RIT with external beam irradiation have been variable and may be indicative of different underlying mechanisms. While the particular experimental model, design and methodology used to compare the efficacy of RIT with external beam irradiation are probably important influences upon subsequent observations, it appears that for a given tumor type, the size of the survival curve shoulder or alpha/beta ratio, and tumor doubling time are important determinants of the magnitude of the dose rate effect. When this effect is minimal, it is possible that other factors such as reoxygenation, the arrest of cells in G2, and selective targeting of tumor by radiolabelled antibody may explain, in part, the increased efficacy of RIT compared with external beam irradiation that has been observed in some systems.

Radiobiologic studies of radioimmunotherapy and external beam radiotherapy in Vitro and in Vivo in human renal cell carcinoma xenografts

Previous studies suggest that the radiobiologic characteristics of in vitro survival curves are important determinants of the response of tumors to both conventional radiotherapy and radioimmunotherapy (RIT). The purpose of this study was to elucidate the relationship between in vitro radiation survival curve parameters and the relative sensitivity of tumor to RIT, exponentially decreasing low dose rate (ED LDR) irradiation and conventional high dose rate (HDR) fractionated external beam radiotherapy.

Radiobiological comparison of external beam irradiation and radioimmunotherapy in renal cell carcinoma xenografts.

Growth delay was measured in TK-82 renal cell carcinoma (RCC) xenografts implanted in nude mice receiving single fraction external beam irradiation (SF-XRT), multifraction external beam irradiation (MF-XRT), or radioimmunotherapy (RIT). Thermoluminescent dosimeter(s) (TLD) and autoradiography were used to ascertain the average absorbed dose delivered and the degree of heterogeneous uptake of radiolabeled antibody for the RIT irradiations. For intravenous administered activities of 100, 200, 400, and 600 microCi of I-131 labeled A6H antibody, volume doubling times (VDT) and TLD absorbed dose measurements for each administered activity were 7 days (341 cGy), 38 days (383 cGy), 85 days (886 cGy) and no regrowth (1034 cGy), respectively. For SF-XRT irradiations of 500, 1000, and 1500 cGy, VDT times were 11, 62, and 103 days, respectively. MF-XRT of 4 X 250 cGy over a 2-week period yielded a VDT of 25 days. Marked peripheral activity deposition was noted on most autoradiographs from multiple tumor samples. These data suggest that an equivalent to superior tumor growth delay is obtained for absorbed doses delivered by exponentially decaying low dose rate radioimmunotherapy RIT compared to similar doses of acute dose rate XRT as quantitated by the TLD method.

Radiobiology of radiolabeled antibody therapy as applied to tumor dosimetry.

This paper reviews the radiobiological aspects of radioimmunotherapy (RIT) with radiolabeled antibodies, including comparisons between RIT and external beam irradiation. The effectiveness of cell killing by radiation decreases with the dose rate and the rate of decrease is determined by the size of the shoulder on the radiation survival curve. Tumors with poor repair capabilities exhibit less of a dose rate effect than tumors with good repair capabilities. Continued tumor cell proliferation during treatment occurs at very low dose rates and can contribute to the reduced effectiveness of low dose rate radiation. Toxicity to normal tissues will determine the total dose of radiolabeled antibody that can be given and this will be influenced by the choice of both the radionuclide and the antibody. The reported enhanced effectiveness of RIT may be due to multiple factors including selective targeting of cells responsible for tumor volume doubling, tumor surface binding rather than homogeneous binding throughout the tumor volume, targeting of the tumor vasculature, or block of cell cycle progression in G2. During RIT, there is less time for reoxygenation of hypoxic tumor cells than during a course of conventional external beam radiotherapy. It has not yet been determined whether this will have a detrimental effect on RIT. Probably the most important factor in the success of RIT is dose heterogeneity. Any viable portion of a tumor that is not targeted and does not receive a significant radiation dose will potentially lead to treatment failure, no matter how high the dose received by the remainder of the tumor. Comparisons between RIT and external beam radiation have shown a wide range of relative efficacy. Tumors most likely to respond to RIT are tumors with poor repair capabilities, tumors that are susceptible to blockage in radiosensitive phases of the cell cycle, tumors that reoxygenate rapidly, and tumors that express the relevant antigen homogeneously. From a radiobiological perspective, it appears that RIT alone is unlikely to cure many tumors and that combination with other treatment modalities will be essential.

Use of the fast Hartley transform for three-dimensional dose calculation in radionuclide therapy

Effective radioimmunotherapy may depend on a priori knowledge of the radiation absorbed dose distribution obtained by trace imaging activities administered to a patient before treatment. A new, fast, and effective treatment planning approach is developed to deal with a heterogeneous activity distribution. Calculation of the three-dimensional absorbed dose distribution requires convolution of a cumulated activity distribution matrix with a point-source kernel; both are represented by large matrices (64 x 64 x 64). To reduce the computation time required for these calculations, an implementation of convolution using three-dimensional (3-D) fast Hartley transform (FHT) is realized. Using the 3-D FHT convolution, absorbed dose calculation time was reduced over 1000 times. With this system, fast and accurate absorbed dose calculations are possible in radioimmunotherapy. This approach was validated in simple geometries and then was used to calculate the absorbed dose distribution for a patients tumor and a bone marrow sample.

Dosimetric considerations in radiation therapy of coin lesions of the lung

PURPOSE The dose distribution in small lung lesions (coin lesions) is determined by the combined effects of reduced attenuation and electronic disequilibrium. The magnitude of the dose delivered also depends on the algorithm used to correct for reduced lung density. These effects are investigated experimentally and computationally for 10 MV photons. METHODS AND MATERIALS Using a polystyrene miniphantom embedded in cork or cedar, thermoluminescent dosimetry and film dosimetry was performed to investigate interface effects and the central dose per monitor unit (MU). Three frequently applied calculation techniques--no density correction, ratio of tissue maximum ratios (TMRs), and the Batho correction--were also used to calculate the dose per MU. The measurements and calculations were compared with a one-dimensional phenomenological theory with parameters taken from the literature. RESULTS The measurements at the entrance surface and center of the miniphantom agreed well with the predictions of the phenomenological theory. The interface regions are usually thin enough (2-3 mm) to be clinically unimportant for 10 MV. Depending on the algorithm used to correct for decreased lung density, the lesion dose may be larger or smaller than the prescribed dose by as much as 20% in extreme cases. A clinical example is presented. CONCLUSIONS In comparing clinical results of treatments of small lung lesions, it is important to be aware of the density correction used.

A new fiducial alignment system to overlay abdominal computed tomography or magnetic resonance anatomical images with radiolabeled antibody single-photon emission computed tomographic scans

Background. The use of computed tomography (CT) or mangetic resonance (MR) to overlay or register uptake patterns displayed by single‐photon emission computed tomography (SPECT) with specific underlying anatomy has the potential to improve image interpretation and decrease diagnostic reading errors. The authors have developed a method that will allow the selection of a region of interest on MR or CT images that correlates with SPECT antibody images from the same patient. This method was validated first in phantom studies and subsequently was used on three patients with suspected colorectal carcinoma.

Radiobiologic studies comparing YTTRIUM-90 irradiation and external beam irradiation in vitro

The purpose of this study was to compare the effectiveness of Yttrium-90 (Y-90) labeled antibody irradiation to 60Co external beam irradiation in vitro by colony formation assay. Two human colon carcinoma cell lines, LS174T, a high CEA producer, and WiDr, a low CEA producer, were exposed to specific activities of Y-90 labeled murine monoclonal anti-CEA antibody ranging from 2.5 to 30 microCi/ml for a fixed period of time. This resulted in calculated doses of 2.25 to 27 Gy and initial dose rates of 2.5 to 29 cGy/hr. Results were compared to similar doses of Y-90 labeled non-specific antibody, unlabeled specific and non-specific antibody, and 60Co external beam irradiation. External beam irradiation studies showed that WiDr, compared to LS174T, was more radioresistant with a larger shoulder to the survival curve, indicating a greater capacity for radiation-induced sublethal damage repair. WiDr was also more radioresistant to Y-90 antibody irradiation. When compared to external beam irradiation, Y-90 labeled antibody irradiation resulted in less cell killing by a factor of 2.4 for LS174T and 3.4 for WiDr. Unlabeled antibody had no significant effect on cell survival. Radiation-induced cell cycle delay experiments demonstrated that WiDr had less cell cycle delay (0.9 to 1.0 min/cGy) compared to LS174T (1.2 min/cGy) after single fraction external beam irradiation. Our results indicate that Y-90 low dose-rate irradiation is radiobiologically less effective in vitro than high dose-rate external beam irradiation by a factor of about 2.4 to 3.4. The results also suggest that the magnitude of this difference depends on the cell lines ability to repair sublethal radiation damage and the degree of cell cycle prolongation after irradiation.