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

Several bone-seeking radiopharmaceuticals, such as ³²P-orthophosphate, ⁸⁹Sr-chloride, ¹⁸⁶Re-1,1 hydroxyethylidene diphosphonate (HEDP), and ¹⁵³Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP), have been used to treat bone pain. The major limiting factor with this modality is bone marrow toxicity, which arises from the penetrating nature of the high-energy β particles emitted by the radionuclides. It has been hypothesized that marrow toxicity can be reduced while maintaining therapeutic efficacy by using radionuclides that emit short-range β particles or conversion electrons. In view of the significant clinical experience with ³²P- orthophosphate, and the similarity in pain relief afforded by ³²P- orthophosphate and ⁸⁹Sr-chloride, this hypothesis is examined in this study using ³²P- and ³³P-orthophosphate in a mouse femur model. Methods: Survival of granulocyte macrophage colony-forming cells (GM-CFCs) in femoral marrow was used as a biologic dosimeter for bone marrow. ³²P- and ³³P- orthophosphate were administered 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 also determined. The biologic dosimeter was calibrated by assessing GM-CFC survival at its nadir after chronic irradiation of Swiss Webster mice with exponentially decreasing dose rates of γ rays (relative biologic effectiveness equivalent to that of β particles) from a low-dose rate ¹³⁷Cs irradiator. Dose-rate decrease half-times (T(d)) (time required for ¹³⁷Cs γ 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 radiopharmaceuticals 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 theoretical 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 exponentially decreasing dose rates of ¹³⁷Cs γ 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 D₃₇ values were 144 (+) 15, 132 (+) 12, 129 (+) 3, and 133 (+) 10 cGy, respectively, compared with a value of 103 cGy for acute irradiation. When ³²P and ³³P were administered, the injected activities required to achieve 37% survival were 313 and 2820 kBq, respectively. Theoretical dosimetry calculations show that ³³P offers a 3- to 6-fold therapeutic advantage over ³²P, depending on the source and target regions assumed. Conclusion: The low-energy β-particle emitter ³³P appears to offer a substantial dosimetric advantage over energetic β- particle emitters (e.g., ³²P, ⁸⁹Sr ¹⁸⁶Re) for irradiating bone and minimizing marrow toxicity. This suggests that low-energy β or conversion electron emitters may offer a substantial advantage for alleviation of bone pain as well as for specifically irradiating metastatic disease in bone.