Tandem dosing of samarium-153 ethylenediamine tetramethylene phosphoric acid with stem cell support for patients with high-risk osteosarcoma

Abstract

Background: Samarium-153 ethylenediamine tetramethylene phosphoric acid (153Sm-EDTMP) is a radiopharmaceutical that has been used to treat osteosarcoma. The authors conducted a phase 2 study to test safety and response of high-risk osteosarcoma to tandem doses of 153Sm-EDTMP and to determine correlation between radiation delivered by low and high administered activities.

Methods: Patients with recurrent, refractory osteosarcoma detectable on standard 99mTc bone scan received a low dose of 153Sm-EDTMP (37.0-51.8 MBq/kg), followed upon count recovery by a second, higher dose (222 MBq/kg). Fourteen days later, patients were rescued with autologous hematopoietic stem cells. The authors assessed response to therapy, performed dosimetry to determine the relationship between administered activity and tumor absorbed dose, and investigated whether changes in 2-(fluorine-18) fluoro-2-deoxy-d-glucose (18F-FDG) tumor uptake upon hematologic recovery reflected disease response.

Results: Nine patients were given tandem doses of 153Sm-EDTMP; 2 received only the initial dose because of disease progression. Six patients experienced radiographic disease stabilization, but this was not considered a response, so the study was terminated early. There was a linear relationship between administered activity and tumor absorbed dose, but there was no correlation between change in 18F-FDG positron emission tomography tumor uptake and tumor absorbed dose or time to progression. The median time to progression for the entire group was 79 days.

Conclusions: Tandem doses of 153Sm-EDTMP were safe for this cohort of heavily pretreated patients with very high-risk disease. The strong correlation between absorbed dose and administered activity within each evaluable patient provides a methodology to individually tailor tandem doses of this agent.

Copyright © 2010 American Cancer Society.

Figures

Figure 1

Tumor absorbed dose versus mass is shown. Tumor absorbed dose was determined after infusion of high-activity samarium-153 ethylenediamine tetramethylene phosphoric acid and compared with tumor mass on a lesion-by-lesion basis for 16 individual tumors from 7 subjects. No correlation was seen (R2 = 0.11, P = .208). Gy indicates grays.

Figure 2

Tumor absorbed dose correlation between low and high administered activities is shown. Tumor absorbed dose of radiation was determined after administration of low- and high-activity samarium-153 ethylenediamine tetramethylene phosphoric acid. There was a linear correlation (slope of the linear regression line is 1.106, and the y intercept is −0.0094), with R2 = 0.74 and P = .006. Gy indicates grays.

Figure 3

Heterogeneity of activity distribution is shown. The fused single-photon emission computed tomography (SPECT)/computed tomography (CT) from Patient 4 (Table 1) shows nonuniform distribution of activity in the large chest wall mass. The top row shows a coronal (left), axial (center), and sagittal (right) CT image. The center row shows corresponding SPECT images, and the bottom row shows the fused images. The extent of the heterogeneity in the distribution of activity is quantified in the histogram (inset). The histogram shows the amount of uptake at 4 hours postinfusion for each voxel in the large anterior tumor. The mean voxel activity (voxel size = 4.42 × 4.42 × 4.42 mm3) at 4 hours was 0.57 MBq, with a standard deviation of 0.71 MBq. This degree of heterogeneity is typical of most tumors quantified with SPECT imaging.

Figure 4

Time to disease progression is shown. A Kaplan-Meier survival curve indicates the number of days from treatment with low-activity samarium-153 ethylenediamine tetramethylene phosphoric acid until the first evaluation that revealed radiographic evidence of progressive disease. PFS indicates progression-free survival.

Figure 5

Comparison between positron emission tomography (PET) response, tumor absorbed dose, and clinical response is shown. (A) The change in PET activity in response to the high administered activity of samarium-153 ethylenediamine tetramethylene phosphoric acid (153Sm-EDTMP) was compared with tumor absorbed dose. For ease of analysis, we determined an standardized uptake value (SUV) ratio, defined as the ratio between the SUVmax post-therapy and the SUVmax pretreatment, both normalized to liver activity. This data transformation allows a logarithmic plot to be evaluated. No correlation between tumor absorbed dose and change in SUV ratio was seen (R2 = 0.051, P = .457). (B) The number of days from treatment with high-activity 153Sm-EDTMP until the first evaluation that revealed radiographic evidence of progressive disease was compared with the response of each tumor as determined by 2-(fluorine-18) fluoro-2-deoxy-d-glucose PET. No correlation is seen between time to tumor progression and SUV ratio (R2 = 0.0031, P = 0.857).