**11.2 Dose fractionation**

184 12 Chapters on Nuclear Medicine

Monoclonal antibodies have inherent limitations for application in targeting methods of

• mAbs are large molecules and so have difficulty in penetrating to large tumor masses

• mAbs are currently not entirely sensitive for malignant tissues. For example, mAb B72.3 recognizes TAG-72 and has been used extensively for the detection of several malignancies including breast, lung, ovary and colorectal (Granowska et al., 1991).

Tumors produce a chaotic vascular system in which blood flow is slow and can be interrupted or even reversed. The ratio of tissue cells to vascular support is lower than most normal tissues. These effects create areas of tumor hypoxia which are relatively resistant to radiation therapy and therefore reduce the efficacy of RIT (Sergides et al., 1999). Some antigens of breast cancer are epithelial surface antigens lying on the inner surfaces of cells, thus being exposed to the circulation only by neoplastic architectural disruption. Other factors influencing the suitability of antigens for tumor targeting are internalization and shedding into the bloodstream. Unfortunately, the majority of identified antigens in human tumors represent tumor-associated antigens, not only present on the tumor tissues, but also

A high background level of radiation due to the presence of radioactivity in normal tissues reduces the tumor/background ratio which reduces the success of diagnosis and therapy. Tumor/background ratio may be diminished by the following factors: (1) the relative long circulation time of nonlocalized murine immunoglobulin in human beings; (2) binding of radiolabeled antibodies to antigens, released by the tumor in the blood pool; (3) the presence of free radionuclides and the subsequent accumulation in kidneys, bladder and other tissues, (4) non-specific uptake antibody by binding Fc fragment of antibody to normal tissues; (5) phagocytosis of murine immunoglobulin especially in the liver; (6) the presence of immune complexes due to the reaction of labelled antibody with Fc cell surface receptors, if non-fragmented immunoglobulins are used and (7) unconjugation of radio-isotope from

**11. Improving in radioimmunoscintigraphy and radioimmunotherapy** 

A variety of methods have been developed to counter the inherent flaws in RIS and RIT techniques. The following section discusses the methods for overcoming these problems.

The pretargeting procedure was developed from the concept that the targeting antibody should be separated from the targeting radionuclide through the use of a bispecific antibody (Chang et al., 2002). An alternative approach to improve tumor:blood ratio for RIS is the use of pre-targeting strategies. The pre-targeting strategies have led to significant improvements in T/B ratio and better diagnostic imaging (Dearling & pedley, 2007). Also, pretargeting has been

especially in the early stages of the malignancies (Sergides et al., 1999).

**10.1 Antibody** 

**10.2 Antigen** 

**techniques** 

**11.1 Pre-targeting** 

imaging and therapy that can be cited in followings:

detectable on normal tissues (Sergides et al., 1999).

antibody in the patient body (Sergides et al., 1999).

**10.3 Background radioactivity** 

Dose fractionation has been proposed as a method to improve the therapeutic effect of radioimmunotherapy (Dearling & pedley, 2007, Denardo et al., 2002). Fractionated radioimmunotherapy may improve therapeutic outcome by decreasing heterogeneity of the dose delivered to the tumor and by decreasing hematologic toxicity, thereby allowing an increased amount of radionuclide that can be administered (Linden et al,. 2005) . A variety of fractionation regimens have been developed and the studies have reported both against and in its favour (Goel et al., 2001; Buchsbaum et al., 1995; Pedley et al., 1993; Schlom et al.,1990; Beaumier et al., 1991). This technique has several advantages including more uniform distribution of mAb and radiation dose, patient-specific radionuclide and radiation dose, control toxicity by titration of an individual patient, reduced toxicity, increased tumor radiation and efficacy and prolongation of tumor response (Violet, 2008). This technique has some disadvantages including lower radiation dose rate, complex strategy to implement, treatment interruption, increased cost and potential delay in tumor regression (Dearling & pedley, 2007).

### **11.3 Delayed imaging**

Kinetic differences in specific and non-specific uptake of radioactivity provide an opportunity to image at a time when the T/B ratio is optimal. Background radioactivity falls with time due to excretion and decay of the radioisotope. Tumor radioactivity also falls with time, but not as fast as the background. The optimum time for RIS is dependent on the selected antibody and radioisotope and detection method (Sergides et al., 1999).
