Tumor dosimetry and response for 153Sm-ethylenediamine tetramethylene phosphonic acid therapy of high-risk osteosarcoma

Abstract

(153)Sm-ethylenediamine tetramethylene phosphonic acid ((153)Sm-EDTMP) therapy for osteosarcoma is being investigated. In this study, we analyzed the influence of (153)Sm-EDTMP administered activity (AA), osteosarcoma tumor density, mass, and the shape of the tumor on absorbed dose (AD). We also studied the biologic implication of the nonuniform tumor AD distribution using radiobiologic modeling and examined the relationship between tumor AD and response.

Methods: Nineteen tumors in 6 patients with recurrent, refractory osteosarcoma enrolled in a phase I or II clinical trial of (153)Sm-EDTMP were analyzed using the 3-dimensional radiobiologic dosimetry (3D-RD) software package. Patients received a low dose of (153)Sm-EDTMP (37.0-51.8 MBq/kg), followed on hematologic recovery by a second, high dose (222 MBq/kg). Treatment response was evaluated using either CT or MRI after each therapy. SPECT/CT of the tumor regions were obtained at 4 and 48 h or 72 h after (153)Sm-EDTMP therapy for 3D-RD analysis. Mean tumor AD was also calculated using the OLINDA/EXM unit-density sphere model and was compared with the 3D-RD estimates.

Results: On average, a 5-fold increase in the AA led to a 4-fold increase in the mean tumor AD over the high- versus low-dose-treated patients. The range of mean tumor AD and equivalent uniform dose (EUD) for low-dose therapy were 1.48-14.6 and 0.98-3.90 Gy, respectively. Corresponding values for high-dose therapy were 2.93-59.3 and 1.89-12.3 Gy, respectively. Mean tumor AD estimates obtained from OLINDA/EXM were within 5% of the mean AD values obtained using 3D-RD. On an individual tumor basis, both mean AD and EUD were positively related to percentage tumor volume reduction (P = 0.031 and 0.023, respectively).

Conclusion: The variations in tumor density, mass, and shape seen in these tumors did not affect the mean tumor AD estimation significantly. The tumor EUD was approximately 2- and 3-fold lower than the mean AD for low- and high-dose therapy, respectively. A dose-response relationship was observed for transient tumor volume shrinkage.

Conflict of interest statement

No other potential conflict of interest relevant to this article was reported.

Figures

FIGURE 1

Example of 3D-RD analysis. Four hours after low-dose 153Sm-EDTMP SPECT for patient 2, 2 tumors were identified (T1 and T2) for dosimetry analysis (A). Density and dose–volume histograms for tumors are also shown. Four hours after high-dose 153Sm-EDTMP SPECT for same patient, 2 new tumors (T3 and T4) were identified in addition to 2 tumors identified at low-dose therapy (B). Tumor density and dose–volume histograms for 2 old tumors (T1 and T2) seen at low-dose therapy are shown for comparison. SPECT images are shown, with same maximum intensity for comparison. AD = absorbed dose.

FIGURE 2

Patient-specific 3D-RD tumor dosimetry analyses. Plots of tumor mass and mean tumor density against mean tumor-absorbed dose per unit administered activity (A and B, respectively) and tumor mass and mean tumor density dependence of equivalent uniform dose (C and D, respectively) are shown. Tumor mass is plotted in logarithmic scale in A and C.

FIGURE 3

Mean absorbed dose calculation based on unit-density sphere model. (A) Power-law fit (dotted line) to OLINDA/EXM dose coefficients against 153Sm-filled homogeneous unit-density spheres of various masses (1–600 g) is demonstrated. 3D-RD–generated dose coefficients are shown as solid point for each sphere on curve fit for comparison. (B) Percentage difference between 3D-RD and OLINDA/EXM for each sphere is given.

FIGURE 4

Comparison of percentage difference in mean absorbed dose estimates between 3D-RD and OLINDA/EXM unit-density sphere model as function of individual patient tumor mass (A), density (B), and sphericity (C). Tumor mass is in logarithmic scale in A.

FIGURE 5

Mean tumor-absorbed dose (left y-axis) and EUD (right y-axis) for individual tumors, plotted against overall radiographic response criteria. PD = progressive disease; SD = stable disease.

FIGURE 6

Plot of percentage volume reduction against mean tumor-absorbed dose (A) or EUD (B).