Case 2 shows constraints and tumor BED for the case where the optimal dosing is not equal to the intersection of the MTD constraints
Case 2 shows constraints and tumor BED for the case where the optimal dosing is not equal to the intersection of the MTD constraints. myeloablative NHL treatment regimens. By plotting the Casein Kinase II Inhibitor IV limiting normal organ constraints as a function of the AAs and calculating tumor biological effective dose (BED) along the normal organ MTBED limits, the optimal combination of activities is usually obtained. The model was tested using previously acquired patient normal organ and tumor kinetic data and MTBED values taken from Casein Kinase II Inhibitor IV the literature. Results The average AA values based solely on normal organ constraints was (19.0 8.2) GBq with a range of 3.9 C 36.9 GBq for 131I-tositumomab, and (2.77 1.64) GBq with a range of 0.42 C 7.54 GBq for 90Y-ibritumomab tiuxetan. Tumor BED optimization results were calculated and plotted as a function of AA for 5 different cases, established using patient normal organ kinetics for the two radiopharmaceuticals. Results included AA ranges which would deliver 95 % of the maximum tumor BED, which allows for informed inclusion of clinical considerations, such as a maximum allowable 131I administration. Conclusions A rational approach for combination radiopharmaceutical treatment has been developed within the framework Casein Kinase II Inhibitor IV of a proven 3-dimensional personalized dosimetry Casein Kinase II Inhibitor IV software, 3D-RD, and applied to the myeloablative treatment of NHL. We anticipate combined radioisotope therapy will ultimately supplant single radioisotope therapy, much as combination chemotherapy has substantially replaced single agent chemotherapy. (or for Zevalin or Bexxar, respectively), (or for lung or liver, respectively), a system of two equations and two unknowns can be set up and solved for the amount of injected activities of 131I-tositumomab, values are positive, it is not possible for both and to be negative solutions to (2), and an optimal answer will exist. An example of this formalism is usually illustrated graphically in Physique 1a using values taken from previously published patient data for 131I-tosituimomab (20) and 90Y-ibritumomab tiuxetan (21), as are all the examples in this manuscript. An MTD value of 27 Gy was chosen for both the liver and the lungs (19). Open in a separate window Physique 1 Optimization based on normal organ MTD (Physique 1a from equation 1) and MTBED (Physique 1b from equations 6 or 8) constraints in AB versus AZ plots. The blue line shows the lungs constraint; the red line shows the liver constraint; the green line is for the kidneys. The lines are solid when they represent the activity limiting constraint, dotted line constraints are automatically satisfied by the solid line criteria BED Constraints The BED (22) relates absorbed dose and absorbed dose rate to the biological effect it would Casein Kinase II Inhibitor IV have if the total absorbed dose were delivered at an infinitesimally low dose-rate. As validation of its biological importance, the BED has been shown be predictive of toxicity thresholds in normal organs (18). Consequently, a model which incorporates radiobiology and more specifically the BED into its constraints is usually more likely to be successful in limiting toxicity. The formula for the BED is usually: and are the organ specific radiobiological parameters from the linear quadratic model of cell survival (23), is the assimilated dose, and is the Lea-Catcheside G-factor: is the DNA repair constant, assuming exponential repair, and and are integration variables. For a simple exponential fit of the dose rate, and according to the following formulae: Snca can stand for any dose-limiting organ and the values still represent the assimilated dose per unit activity for Bexxar (and (and and plotting as a function of (or vice versa) a graphical representation of equation (6) is usually obtained; these are shown in Physique 1b using the same measured patient parameters as for Physique 1a but with MTBED constraints of 30 Gy for the lungs and 35 Gy for the liver. Note that we have included the kidneys as a possible limiting organ although in this illustrative example the kidney constraints will always be met if the lung and liver constraints are met. The equations derived from equation (6) that are graphed in Physique 1b are: can stand for any dose-limiting organ (lungs, liver and kidneys in Physique 1b). The limiting constraints are shown in solid color in Physique 1:.