Marrow toxicity of P-33- versus P-32-orthophosphate: Implications for therapy of bone pain and bone metastases

Several bone-seeking radiopharmaceuticals, such as P-32-orthophosphate, Sr- 89-chloride, Re-186-1,1 hydroxyethylidene diphosphonate (HEDP), and Sm-153- ethylene diamine tetramethylene phosphonic acid (EDTMP), have been used to treat bone pain. The major limiting factor with this modality is bone marro w toxicity, which arises from the penetrating nature of the high-energy bet a particles emitted by the radionuclides. It has been hypothesized that mar row toxicity can be reduced while maintaining therapeutic efficacy by using radionuclides that emit short-range beta particles or conversion electrons . In view of the significant clinical experience with P-32-orthophosphate, and the similarity in pain relief afforded by P-32-orthophosphate and Sr-89 -chloride, this hypothesis is examined in this study using P-32- and P-33-o rthophosphate in a mouse femur model. Methods: Survival of granulocyte macr ophage colony-forming cells (GM-CFCs) in femoral marrow was used as a biolo gic dosimeter for bone marrow. P-32- and P-33-orthophosphate were administe red intravenously, and GM-CFC survival was determined as a function of time after injection and, at the nadir, as a function of injected activity. The kinetics of radioactivity in the marrow, muscle, and femoral bone were als o determined. The biologic dosimeter was calibrated by assessing GM-CFC sur vival at its nadir after chronic irradiation of Swiss Webster mice with exp onentially decreasing dose rates of gamma rays (relative biologic effective ness equivalent to that of beta particles) from a low-dose rate Cs-137 irra diator. Dose-rate decrease half-times (T-d) (time required for Cs-137 gamma ray dose rate to decrease by one half) of 62, 255, and 425 h and infinity were used to simulate the dose rate patterns delivered by the radiopharmace uticals as dictated by their effective clearance half-times from the mouse femurs. These data were used to experimentally determine the mean absorbed dose to the femoral marrow per unit injected activity. Finally, a theoretic al dosimetry model of the mouse femur was developed, and the absorbed doses to the femoral marrow, bone, and endosteum were calculated using the EGS4 Monte Carlo code. Results: When the animals were irradiated with exponentia lly decreasing dose rates of Cs-137 gamma rays, initial dose rates required to achieve 37% survival were 1.9, 0.98, 0.88, and 0.79 cGy/h for dose rate decrease half-times of 62, 255, and 425 h and infinity, respectively. The D-37 values were 144 +/- 15, 132 +/- 12, 129 +/- 3, and 133 +/- 10 cGy, res pectively, compared with a value of 103 cGy for acute irradiation. When P-3 2 and P-33 were administered, the injected activities required to achieve 3 7% survival were 313 and 2820 kBq, respectively. Theoretical dosimetry calc ulations show that P-33 offers a 3- to 6-fold therapeutic advantage over P- 32, depending on the source and target regions assumed. Conclusion: The low -energy beta-particle emitter P-33 appears to offer a substantial dosimetri c advantage over energetic beta-particle emitters (e.g., P-32, Sr-89 Re-186 ) for irradiating bone and minimizing marrow toxicity. This suggests that l ow-energy beta or conversion electron emitters may off era substantial adva ntage for alleviation of bone pain as well as for specifically irradiating metastatic disease in bone.