Principles of Therapy with Unsealed Sources

Janet F. Eary

Division of Nuclear Medicine, Department of Radiology, University of Washington, Seattle, Washington, U.S.A.

INTRODUCTION

Since the discovery of radium by Madame Curie in the early twentieth century, it has been the dream of medical practitioners to use radioactive emissions for treatment of human disease. Indeed, Madame Curie and her coworkers found that certain superficial skin diseases underwent dramatic responses after exposure to radiation and the fields of radiobiology and radiation oncology were born (1). In the 30 years post-World War II, many new radioisotopes were discovered and purified for medical use. In fact, medical radioisotope therapy use and research has paralleled the development of all other uses of atomic energy. Colloidal gold and phosphorous (P-32) were some of the earliest radioisotopes used in therapy (2). The discovery of a myriad of new radioisotopes for medical use followed rapidly, along with new radiochemistry procedures for labeling drugs and biologic agents. The history of therapy with unsealed sources can trace its roots to the beginnings of the atomic age, the birth of radiochemistry as a discipline, radioimmunoassay, and modern nuclear medicine imaging.

PRINCIPLES OF THERAPY

Radionuclide therapy with unsealed sources has several underlying principles, which apply most to all forms of treatment. Where a treatment using a

Table 1 Important Characteristics of Therapeutic Radionuclides

Type and energy of emissions Half-life

Chemical behavior radionuclide is envisioned, it ideally represents a radioisotope-drug combination that is specifically suited for a disease in an individual patient. To begin with, the physical characteristics of the radioisotopes must be considered (Table 1). Critical characteristics include type and range of emissions, half-life, and chemical characteristics (Chapter 2). Most therapy agents utilize ¡-particle emissions for their ability to penetrate tissues. This deposition of energy in tissue by 3 emitters results in cellular damage. Among the 3 emitters there are several choices with respect to energy of the 3 emission. Lower energy 3 particles can travel a few cell diameters, or at most in the sub-millimeter range. These may be useful for microscopic targets and reducing normal tissue damage. Higher energy 3 particles such as those emitted by P-32, Y-90, and Ho-166 have excellent tissue penetration with a range beyond the source of several millimeters. This may be desirable when a high homogeneous dose to a large target such as a lymphoma nodule or the bone from a bone surface or marrow source is being treated. Intermediate-range 3 particles such as those from iodine-131 (I-131) have a

200 400 600 800

Maximum Dose = 0.67 Gy Average Dose = 0.49 Gy Minimum Dose = 0,49 Gy

Dose

0.65

0.55

200 400 600 800

0.45

0.45

Maximum Dose = 0.67 Gy Average Dose = 0.49 Gy Minimum Dose = 0,49 Gy

Figure 1 Calculated dose homogeneity distribution from an iodine-131-labeled anti-B cell antibody in a nodular lymphoma. Shading levels represent absorbed dose levels of the radiation, which vary considerably at the microscopic level.

Figure 2 Iodine-131 anti-B cell antibody localization observed in a patient with a large abdominal tumor on day 6 after infusion. On day 1 (left) and day 6 (right).

shorter path length and may result in less dose homogeneity to the tissue (Fig. 1), but still retain excellent therapeutic effect. Proponents of Auger emitters for radionuclide therapy posit that these low-energy ¡3 particles can cause therapeutic effect without excess tissue toxicity because of their short energy deposition range. A somewhat similar argument has garnered favor for support of the use of a-particle emitters for therapy. At-111, Bi-213, and some of the transuranic elements have been studied with varying degrees of success. a particles are highly energetic with these emitters. Investigators hypothesize that the heavy a particle has such momentum that it results in high levels of cell killing close to the origin of the radionuclide deposition. This is thought to result in low surrounding tissue toxicity and high levels of cell killing in tumors where the radiation is deposited. Gamma emissions from therapeutic radionuclides such as the 364 KeV in I-131 are energetic enough to cause a generalized dose effect in an organ, or in the whole body and should be considered in treatment planning for the enhanced treatment effect they might provide as well as the toxicity they may cause (Fig. 2).

The physical half-life of the therapeutic radionuclide is an important consideration and underlying principle for therapy planning. Rarely, except in thyroid treatment, is the simple salt form of the radionuclide used. It is most likely attached to a drug or particle that controls its biodistribution. The ideal therapeutic radiopharmaceutical is one that remains attached to the parent drug or its metabolites, and is excreted rapidly through a known simple route. Radio-pharmaceuticals that undergo complex metabolism that results in free radio-nuclides as well as labeled metabolites that are excreted by several routes are more difficult to use. They also create greater difficulty for realistic radiation absorbed dose estimation based on their observed biodistribution. In most cases, the most optimal combination is a radionuclide with a physical half-life that is similar to the drug or biologic agent half-life, so that the resulting effective half-life represents a length of time appropriate for maximum therapeutic effect and minimal nontarget toxicity.

Many therapeutic radionuclides are radiometals and therefore pose challenges for radiopharmaceutical design. These radiometals often have large atomic radii and can be difficult to chelate or chemically attach to drugs and biologic agents. Weak chelation associations can result in transchelation to naturally occurring metalloproteins. This can result in undesired biodistribution of radiome-tal away from target sites. Certainly the chemical behavior of the therapeutic radionuclide contributes a great deal to ease of preparation, stability, and biological behavior in the patient. A special case is in the use of a emitters where radionuclide daughters, being different elements may have different chemical characteristics with respect to the radiolabeling strategy compared with the parent.

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