Clinical Trial Design and Scoring of Radionuclide Therapy Endpoints: Normal Organ Toxicity and Tumor Response

Abstract

Like other cancer therapy agents under development, radionuclide therapies are usually evaluated in a progressive series of clinical trials after basic science, human cell culture and animal model studies. Toxicities during these trials are graded using common scoring systems that are in widespread use such as the Common Toxicity Criteria from the National Cancer Institute. Information on normal tissue toxicity from radionuclides is more limited than that from external beam radiation and is more variable. Variability is likely due to many biologic factors as well as less precise dose quantitation than those used in external beam radiation practice. As expected based on known radiobiologic effects, tolerance to radionuclide therapy appears to exceed that from high dose rate external beam radiation in most organs. Although the correlation between reported dose estimates and toxicity has progressively and substantially improved over the past two decades, further progress is needed to establish optimal toxicity predictive relationships. Continued refinement of dosimetry techniques and standardization is expected to increase the accuracy and comparability of radiation dose reports between institutions as well as improve dose/response correlation.

Prediction of Therapy Tumor-Absorbed Dose Estimates in I-131 Radioimmunotherapy Using Tracer Data Via a Mixed-Model Fit to Time Activity

“…5 On the other hand, a review article has summarized a considerable variation between dose estimates predicted from post-tracer imaging compared to those obtained from post-therapy imaging of the same patient. 6 These limited previous studies were carried out using two-dimensional (2D) planar-imaging methods, which can be suboptimal due to the inability to accurately correct for interference from activity in overlying and underlying tissues. Quantitative three-dimensional (3D) SPECT imaging provides major advantages over 2D planar methods of activity quantification and the potential for improved dosimetric accuracy.…”

A two-tiered physiologically based model for dually labeled single-chain Fv-Fc antibody fragments

“…LS174T human colorectal tumor cells were flank injected into mice 10 days before (t = À10 days) administering radiolabeled antibody. 4 Tumor mass at t = 0 ranged from 0.003 to 0.229 g (median mass = 0.05 g, n = 20). Mice in each of four experimental groups (n = 5) were sacrificed at the following timed data points: 0, 2, 4, 6, 12, 24, 48, and 72 hours.…”

“…For example, Ibritumomab tiuxetan is an 90 Y-labeled mAb that binds specifically to CD20 (1, 2), a transmembrane protein expressed exclusively on both normal B cells and certain B cell -derived tumor cells, resulting in localization of mAb to tumor sites where 90 Y emits h-radiation capable of killing cells adjacent to the target cell (2). The benefit of this type of therapy is that tumor cells that do not express the target protein (e.g., CD20) can still be eliminated; however, exposure of healthy tissues to radiation is a major concern (3,4). Effective tumor doses have been shown to be highly variable in clinical trials, ranging from 16 to 14,000 cGy, with toxicity reported following exposure of liver, stomach, bowel, kidneys, and lungs to doses ranging from 1,000 to 8,000 cGy, delivered by therapeutic doses of a variety of radionuclides (4).…”

“…The benefit of this type of therapy is that tumor cells that do not express the target protein (e.g., CD20) can still be eliminated; however, exposure of healthy tissues to radiation is a major concern (3,4). Effective tumor doses have been shown to be highly variable in clinical trials, ranging from 16 to 14,000 cGy, with toxicity reported following exposure of liver, stomach, bowel, kidneys, and lungs to doses ranging from 1,000 to 8,000 cGy, delivered by therapeutic doses of a variety of radionuclides (4). Bone marrow is especially sensitive to radiation, with toxicity reported following doses of 10 to 200 cGy (4).…”

“…Effective tumor doses have been shown to be highly variable in clinical trials, ranging from 16 to 14,000 cGy, with toxicity reported following exposure of liver, stomach, bowel, kidneys, and lungs to doses ranging from 1,000 to 8,000 cGy, delivered by therapeutic doses of a variety of radionuclides (4). Bone marrow is especially sensitive to radiation, with toxicity reported following doses of 10 to 200 cGy (4).…”