Clinical Radioimmunotherapy and Systemic Targeted Radiopharmaceutical Therapy (STaRT) Programs in a Radiation Oncology Environment

Radioimmunotherapy (RIT) is a relatively new area of clinical oncology in which patients are treated with a biologically targeted radiopharmaceutical combining a tumor-selective monoclonal antibody radiolabeled with a highenergy radionuclide (typically a medium-range beta emitter). To date, 2 of these therapeutic RIT compounds have received full clearance by the Food and Drug Administration, both indicated for the management of relapsed and refractory CD20-positive low-grade B-cell non-Hodgkin lymphoma (NHL) and related conditions. These 2 compounds (Y ibritumomab tiuxetan or “Zevalin” and I tositumomab or “Bexxar”) are now beginning to play major roles in lymphoma therapy. Both of these compounds are selective for the CD20 surface antigen found on greater than 95% of B-cell NHL as well as essentially all normal mature B cells. Although the antibody selectivity for these 2 radiopharmaceuticals is, to a first approximation, fairly similar, the pattern of use and clinical infrastructures required to deliver these 2 agents safely are somewhat different as a result of the difference in therapeutic isotopes (Table 1). Both of these targeted radiopharmaceuticals are probably best delivered as a team exercise involving 3 different academic departments: hematology/oncology, nuclear medicine, and radiation oncology. In addition, a host of support personnel combine their efforts to facilitate a comprehensive RIT program. Figure 1 presents a cartoon of Y ibritumomab tiuxetan (Zevalin) in schematic form. This radiopharmaceutical incorporates the pure beta emitting radiometal Y into a chemical cage (“chelate”) sidearm chain covalently attached to the backbone of the antibody. The high-energy beta particle emissions produced by this isotope penetrate several millimeters in tissue but can be blocked easily by routine plastic shielding several millimeters thick. For this reason, very little of the radioactivity produced by these RIT agents escapes from the body of the infused patient and the extra radiation safety precautions are fairly minimal. Except for a few special situations, the radiation safety precautions necessary for the clinical use of Y Zevalin are essentially identical to the panel of typical “universal precautions” now observed for all bodily fluids encountered in routine hospital care. Because the physical half-life of Y is approximately 2.7 days and the biologic half-life of the Y antibody complex is approximately 1 day, the period during which the infused patient is significantly radioactive is no more than a few days, and treatment is almost always outpatient. Virtually all of the acute side effects are caused by potential immunologic reactions to the murine antibody itself rather than to the radiopharmaceutical or the side-chain linkers on the antibody. Figure 2 presents a cartoon of I tositumomab (Bexxar). Similar to Y Zevalin, the I Bexxar shows target selectivity for the CD20 surface antigen and its approved clinical use is currently limited to at refractory lowgrade B-cell NHL and related conditions. However, in contrast to the Y Zevalin, the I Bexxar incorporates a medium-energy mixed-spectrum beta/gamma emitter with a convenient gamma emission at 364 kev. This emission is suitable for imaging on a properly collimated gamma camera, in contrast to the Y Zevalin, which is not well detected on a gamma camera and therefore requires a surrogate imaging isotope (Indium-111) to be incorporated into the Zevalin framework to allow positional localization. The penetrating gamma rays from the I and the approximately 8-day half-life also require significantly more radiation safety provisions and more rigorous attention to minimizing the radiation exposure of hospital personnel, patient families, and the environment. However, the creation of an integrated multidepartment RIT team should allow a radiation oncology program to handle the delivery of I-131 Bexxar in a safe, efficient, and effective manner. Figure 3 shows in outline From the Department of Radiation Oncology/T28, The Cleveland Clinic, Cleveland, Ohio. Dr. Macklis has received financial support for clinical trials from Biogen Idec and GSK. He is professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and a staff member in the Department of Radiation Oncology at Cleveland Clinic. Reprints: Roger M. Macklis, MD, Department of Radiation Oncology/T28, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: macklir@ccf.org. Copyright © 2006 by Lippincott Williams & Wilkins ISSN: 0277-3732/06/2906-0543 DOI: 10.1097/01.coc. 0000248941.97523. b2