Method of establishing the optimal radiation dose

Details Method of establishing the optimal radiation dose Method of establishing the optimal radiation dose

1996-01-11

2001-06-26

Hartley, Michael G. (Department: 1619)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

C424S001490, C600S001000, C600S003000

Reexamination Certificate

active

06251362

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the administration of radiopharmaceutical compounds for the therapy of disease including cancer. More particularly, the present invention relates to a method of establishing the optimal effective radiation dose for treatment of disease, the method minimizing toxicity while preserving therapeutic activity.
2. Description of the Relevant Art
Radiopharmaceuticals are compounds composed of radioactive isotopes often bound to other molecules. These radiopharmaceuticals are used in assessing the presence, outline, size, position, or physiology of individual organs or tissues. More significantly for the present invention, radiopharmaceuticals are commonly used in the treatment of disease. For example, radioactive iodine (I-131) is used to treat thyroid cancer or overactive thyroids (Grave's disease). Of considerable importance is the development of monoclonal antibodies having attached radioactive labels. When combined with antibodies that are relatively specific for a particular diseased tissue, such antigen-specific monoclonal antibodies are able to selectively direct comparatively sizable amounts of radiation to the specific disease site. Such treatments are being applied to the treatment of non-Hodgkin's lymphomas, Hodgkin's lymphomas, Hepatoma, colorectal cancer, brain tumors, and many other forms of cancer. In addition, the treatments also have the potential to treat other types of disease, including auto-immune conditions such as, for example, Systemic Lupus and Rheumatoid arthritis. Targeted radiopharmaceutical therapy may be ultimately be found to be broadly applicable to a wide variety of neoplastic and benign diseases.
At present, the radiopharmaceutical is commonly introduced into the blood for ultimate internal distribution through conventionally known methods such as through intravenous, inhalation, or oral administration. A common unit of radioactivity is the millicurie, or mCi.
The general difficulty of the administration of radiopharmaceuticals for therapy lies in the fact that if the patient is given too much radioactivity, toxicity results. On the other hand, it is necessary to give enough of the radiopharmaceutical so that the disease is successfully treated.
The most common specific side effect of radiopharmaceutical treatment is bone marrow suppression or ablation. This is caused by the targeting of the radiopharmaceutical (or the radiolabel) to the bone or bone marrow or is due to circulation of the radioantibody through the blood vessels (including the marrow). In general, this situation could lead to bleeding, infection or death. This side effect (as well as other undesirable side effects) is caused by the inaccuracy of known methods used to determine the radioactive dose for the individual patient. For example, up to a five fold difference in the radiation dose to blood, bone marrow, or body received/mCi of the particular radioantibody administered may exist between patients. (Radiation dose is defined as the total amount of energy per unit mass deposited in an individual as a result of radioactive decay.) These differences are tied to the fact that individuals are physiologically different. Not only are individuals of different sizes and, to some degree, densities, they also differ in abilities to metabolize and clear radiopharmaceuticals. For example, if the radioactivity is attached to a monoclonal antibody, the radioactivity might be eliminated from different patients such that a half life of clearance of radioactivity of three days might be identified in a first patient, while a half life of clearance of radioactivity of six days is identified in a second patient.
Accordingly, the challenge facing the physician today is determining the correct number of millicuries to be administered to a particular patient having a particular disease at a particular stage of development of that disease. The number of millicuries to be administered is based on the prescription of a given radiation dose to the “whole body” of the patient, which is dependent upon several factors, including the patient's size and the rate of disappearance of radioantibody from the body as determined by direct measurements of the biodistribution of a tracer dose (a small, non-therapeutic quantity) of radioactivity using a gamma camera, probe detector system, or other radiation detection system. Using such an approach, a “whole body radiation dose” can be calculated from the tracer doses, which can be used to predict the radiation dose the “whole body” would receive from subsequent radiopharmaceutical therapy and which allows the radiation dose administered to be effective. Initial results with this approach using the anti-B-1 antibody have shown excellent therapeutic efficacy and modest toxicity. Results of clinical studies with this approach are detailed in NEJM 7:329, pp. 459-465, 1993 (Kaminski et al.), J. Nucl. Med. 35(5), 233P, 1994 (Wahl et al.), and J. Nucl. Med. 35(5), 101P, 1994 (Wahl et al.).
While this approach to calculating “whole body” radiation dose represents a major improvement over other methods which are not individualized to the patient's individual pharmacology, it still does not fully overcome the difficulties related to the accurate calculation of optimal radiation doses to treat radiosensitive tumors. The inherent failure of this method lies in the fact that the simple assumptions of “whole body” dose are not fully valid in terms of human patient physiology. Accordingly, while radiotoxicity is reduced, it is not fully eliminated or even absolutely minimized. Part of the reason for this failure is that the “whole body” dose approach assumes that a radiopharmaceutical is uniformly distributed throughout the body. There is an assumption underlying this thinking that the body is uniform, and that distribution of chemicals in the body is likewise uniform. This is not the case, as most radiopharmaceuticals, particularly intact monoclonal antibodies, have very limited accumulation in fat tissue compared to considerably greater accumulation in lean body tissue (including bone marrow).
In an effort to improve the accuracy of radiopharmaceutical mCi dosage, a method has been developed that utilizes a parameter directed to “total body dose-lean” (TBD-lean) to account for the fact that individuals may be modeled as an outer shell of fat (where little radioantibody or radiopharmaceutical accumulation occurs) which surrounds an active lean body mass, including bone marrow. This method is disclosed in the present inventors' co-pending application entitled METHOD FOR THE REDUCTION OF TOXICITY OF RADIOPHARMACEUTICAL THERAPY, Ser. No. 08/433,674, filed on May 4, 1995. As set forth in the co-pending application, by appreciating the fact that in man there is a “lean body” within a “fat” outer shell, a formula may be used to estimate what percentage of the person is fat and what percent of the person is lean. Thereafter, the radioactivity is traced as essentially being distributed uniformly and totally through the lean component. By first estimating what fraction of the body is lean and then calculating the radioactivity distribution within a given lean volume, the proper dose of radiopharmaceutical for treatment without undue toxicity can be administered on an individualized, case-by-case basis.
While resolving many of the difficulties related to the prescription of effective amounts of radiation doses, the prior art nevertheless may be improved upon.
SUMMARY OF THE PRESENT INVENTION
The present invention is directed to a method for determining the number of millicuries of radioactivity to be administered to a patient so as to establish a given centigray (cGy) dose to either the patient's lean body or the patient's total body. According to the present invention, the following steps are followed.
Initially the rate of clearance or disappearance of radioactivity from a patient is determined by direct measurement across multiple time points using a radiation detec

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