A phase I trial of humanized monoclonal antibody A33 in patients with colorectal carcinoma: biodistribution, pharmacokinetics, and quantitative tumor uptake.

PURPOSE: To determine the in vivo characteristics of huA33, a CDR-grafted humanized antibody against the A33 antigen, we have conducted an open-label, dose escalation, biopsy-based phase I trial of huA33 in patients with colorectal carcinoma. EXPERIMENTAL DESIGN: Patients with colorectal carcinoma were infused with [131I]huA33 (400 MBq: 10 mCi) and [125I]huA33 (40 MBq: 1 mCi) 1 week before surgery. There were four huA33 dose levels (0.25, 1.0, 5.0, and 10 mg/m2). Adverse events, pharmacokinetics, biodistribution, tumor biopsies, and immune responses to huA33 were evaluated. RESULTS: There were 12 patients entered into the trial (6 males and 6 females; age range, 39-66 years). No dose-limiting toxicity was observed. The biodistribution of huA33 showed excellent uptake of [131I]huA33 in metastatic colorectal carcinoma. Pharmacokinetic analysis showed no significant difference in terminal half-life (T1/2beta) between dose levels (mean +/- SD, 86.92 +/- 22.12 hours). Modeling of colon uptake of huA33 showed a T1/2 of elimination of 32.4 +/- 8.1 hours. Quantitative tumor uptake ranged from 2.1 x 10(-3) to 11.1 x 10(-3) %ID/g, and tumor/normal tissue and tumor/serum ratios reached as high as 16.3:1 and 4.5:1, respectively. Biosensor analysis detected low-level human anti-human antibody responses in four patients following huA33 infusion. CONCLUSIONS: huA33 shows selective and rapid localization to colorectal carcinoma in vivo and penetrates to the center of large necrotic tumors, and colon elimination half-life of huA33 is equivalent to basal colonocyte turnover. The excellent targeting characteristics of this humanized antibody indicate potential for the targeted therapy of metastatic colorectal cancer in future trials.

Phase I trial of 131I-huA33 in patients with advanced colorectal carcinoma.

PURPOSE: Humanized monoclonal antibody A33 (huA33) targets the A33 antigen which is expressed on 95% of colorectal cancers. A previous study has shown excellent tumor-targeting of iodine-131 labeled huA33 (131I-huA33). Therefore, we did a phase I dose escalation trial of 131I-huA33 radioimmunotherapy. EXPERIMENTAL DESIGNS: Fifteen patients with pretreated metastatic colorectal carcinoma each received two i.v. doses of 131I-huA33. The first was an outpatient trace-labeled "scout" dose for biodistribution assessment, followed by a second "therapy" dose. Three patients were treated at 20, 30, and 40 mCi/m2 dose levels, and six patients at 50 mCi/m2 to define the maximum tolerated dose. RESULTS: Hematologic toxicity was 131I dose-dependent, with one episode of grade 4 neutropenia and two episodes of grade 3 thrombocytopenia observed at 50 mCi/m2. The maximum tolerated dose was determined to be 40 mCi/m2. There were no acute infusion-related adverse events, and gastrointestinal toxicity was not observed despite uptake of 131I-huA33 in bowel. Seven patients developed pruritus or rash, which was not related to 131I dose. There was excellent tumor-targeting of 131I-huA33 shown in all patients. The serum T1/2beta of 131I-huA33 was (mean +/- SD) 135.2 +/- 46.9 hours. The mean absorbed tumor dose was 6.49 +/- 2.47 Gy/GBq. Four patients developed human anti-human antibodies. At restaging, 4 patients had stable disease, whereas 11 patients had progressive disease. CONCLUSION: Radioimmunotherapy using 131I-huA33 shows promise in targeting colorectal tumors, and is deliverable at a maximum tolerated dose of 40 mCi/m2. Further studies of 131I-huA33 in combination with chemotherapy are planned.

Radiation dose to PET technologists and strategies to lower occupational exposure.

OBJECTIVE: The use of PET in Australia has grown rapidly. We conducted a prospective study of the radiation exposure of technologists working in PET and evaluated the occupational radiation dose after implementation of strategies to lower exposure. METHODS: Radiation doses measured by thermoluminescent dosimeters over a 2-y period were reviewed both for technologists working in PET and for technologists working in general nuclear medicine in a busy academic nuclear medicine department. The separate components of the procedures for dose administration and patient monitoring were assessed to identify the areas contributing the most to the dose received. The impact on dose of implementing portable 511-keV syringe shields (primary shields) and larger trolley-mounted shields (secondary shields) was also compared with initial results using no shield. RESULTS: We found that the radiation exposure of PET technologists was higher than that of technologists performing general nuclear medicine studies, with doses averaging 771 +/- 147 and 524 +/- 123 microSv per quarter, respectively (P = 0.01). The estimated dose per PET procedure was 4.1 microSv (11 nSv/MBq). Injection of 18F-FDG contributed the most to radiation exposure. The 511-keV syringe shield reduced the average dose per injection from 2.5 to 1.4 microSv (P < 0.001). For the longer period of dose transportation and injection, the additional use of the secondary shield resulted in a significantly lower dose of radiation than did use of the primary shield alone or no shield (1.9 vs. 3.6 microSv [P = 0.01] and 3.4 microSv [P = 0.03], respectively). CONCLUSION: The radiation doses currently received by technologists working in PET are within accepted occupational health guidelines, but improved shielding can further reduce the dose.

An evaluation of the shielding effectiveness of lead aprons used in clinics for protection against ionising radiation from novel radioisotopes.

The purpose of this study is to evaluate the effectiveness of personal radiation shields currently worn in hospital and other diagnostic environments. This study was performed with four different radioisotopes; (18)F, (99m)Tc, (124)I and (131)I. (18)F results showed a decrease in dose with 0.5-mm Pb shielding but the reduction provided does not warrant its use clinically. (124)I testing demonstrated that dose enhancement can occur in greater shield thicknesses. PET isotope (124)I can be adequately shielded using 0.25-mm Pb equivalent aprons but any higher thickness increase the wearer's dose. As a result more shielding does not always equal more protection. The (131)I test showed that no dose reduction occurred, even when tested with up to 1.25-mm Pb equivalent shielding. Novel radioisotopes being used in the laboratory and clinic should be individually tested as each requires specific shielding testing.

Computed tomography overexposure as a consequence of extended scan length.

INTRODUCTION: This study aimed to raise awareness around the increased effective dose as scan length chosen is increased from standard protocol METHODS: The Monte Carlo-based software CT-Expo (G. Stamm (Medizinische Hochschule Hannover, Hannover, Germany) and H.D. Nagel (SASCRAD, Buchholz, Germany)) was used to simulate the effective dose increase as the scanned region of the standard protocol increased. RESULTS: The results of this study show that for scans with a high computed tomography dose index (CTDI)vol the patient could be exposed to an extra 1 mSv within 6 cm of overscan. Protocols that investigated large scan areas may not see a significant relative dose reduction because of the use of a lower CTDIvol ; however, radiation exposure should be kept as low as reasonably achievable. CONCLUSION: There is significant dose optimisation potential when strictly adhering to appropriate scan lengths within each imaging protocol wherever possible.

Effects of radiographic techniques on the low-contrast detail detectability performance of digital radiography systems.

PURPOSE: To evaluate the effects of the radiation exposure factors kilovolt peak and tube current time (milliampere seconds) on the low-contrast detail detectability performance of 3 types of planar digital radiography systems. Detectability performance of an imaging system refers to its ability to detect and present the low-contrast details of organs in the acquired image. The authors also compare detectability performance between computed radiography, indirect digital radiography, and direct digital radiography by evaluating low-contrast details of the obtained images. METHODS: A low-contrast detail phantom was inserted within 10-cm thicknesses of Perspex plastic sheets. The images were obtained with various kilovolt peak and milliampere second settings for each of the 3 digital radiography systems. Artinis CDRAD Analyser software was used to score the images and calculate the inverse image quality figure (IQFinv). RESULTS: The higher milliampere second levels in each kilovolt peak selection resulted in higher IQFinv in computed radiography and indirect and direct digital radiography. IQFinv values significantly increased in indirect digital radiography with increasing kilovolt peak in only 1 and 2 mAs. There were insignificant differences in IQFinv values when altering kilovolt peak in each milliampere second level in direct digital radiography. The indirect digital radiography system generally demonstrated better detectability performance than computed radiography and direct digital radiography. However, direct digital radiography demonstrated better detectability performance than indirect digital radiography at lower kilovolt peak and milliampere second settings, as did computed radiography at lower kilovolt peak settings. DISCUSSION: Higher milliampere second settings increase photon count, which results in a higher signal-to-noise ratio and thus increased detectability. Lower milliampere second settings increase noise level on images, which increases the risk of diagnostic detail loss. Changing the kilovolt peak at the different milliampere second settings essentially did not affect the IQFinv of the different digital radiography systems. CONCLUSION: Increasing milliampere seconds in all digital imaging systems generally improves detectability performance. However, altering the kilovolt peak setting does not significantly change the IQFinv and detectability of objects in a digital radiograph. Imaging system selection should be based on typical radiographic examinations. Indirect digital radiography systems are better for studies that require higher kilovolt peak, such as large organs, and direct digital radiography is better for studies that require low kilovolt peak, such as small organs and mammography, which is used to examine fine tissue details.