131I-tositumomab radioimmunotherapy: initial tumor dose-response results using 3-dimensional dosimetry including radiobiologic modeling

Abstract

For optimal treatment planning in radionuclide therapy, robust tumor dose-response correlations must be established. Here, fully 3-dimensional (3D) dosimetry was performed coupling SPECT/CT at multiple time points with Monte Carlo-based voxel-by-voxel dosimetry to examine such correlations.

Methods: Twenty patients undergoing (131)I-tositumomab for the treatment of refractory B-cell lymphoma volunteered for the study. Sixty tumors were imaged. Activity quantification and dosimetry were performed using previously developed 3D algorithms for SPECT reconstruction and absorbed dose estimation. Tumors were outlined on CT at multiple time points to obtain absorbed dose distributions in the presence of tumor deformation and regression. Equivalent uniform dose (EUD) was calculated to assess the biologic effects of the nonuniform absorbed dose, including the cold antibody effect. Response for correlation analysis was determined on the basis of the percentage reduction in the product of the largest perpendicular tumor diameters on CT at 2 mo. Overall response classification (as complete response, partial response, stable disease, or progressive disease) used for prediction analysis was based on criteria that included findings on PET.

Results: Of the evaluated tumor-absorbed dose summary measures (mean absorbed dose, EUD, and other measures from dose-volume histogram analysis), a statistically significant correlation with response was seen only with EUD (r = 0.36 and P = 0.006 at the individual tumor level; r = 0.46 and P = 0.048 at the patient level). The median value of mean absorbed dose for stable disease, partial response, and complete response patients was 196, 346, and 342 cGy, respectively, whereas the median value of EUD for each of these categories was 170, 363, and 406 cGy, respectively. At a threshold of 200 cGy, both mean absorbed dose and EUD had a positive predictive value for responders (partial response + complete response) of 0.875 (14/16) and a negative predictive value of 1.0 (3/3).

Conclusion: Improved dose-response correlations were demonstrated when EUD incorporating the cold antibody effect was used instead of the conventionally used mean tumor-absorbed dose. This work demonstrates the importance of 3D calculation and radiobiologic modeling when estimating absorbed dose for correlation with outcome.

FIGURE 1

SPECT/CT images showing uptake in an inguinal tumor at day 0 after tracer, day 2 after therapy, and day 8 after therapy.

FIGURE 2

Response at 2 mo plotted against mean tumor-absorbed dose (A) and EUD (B), at tumor level (n = 57).

FIGURE 3

Response at 2 mo (based on sum of products (SPDs) of perpendicular tumor diameters) plotted against mean tumor-absorbed dose (A) and EUD (B), at patient level (n = 19). Dose values were averaged over multiple tumors of each patient.

FIGURE 4

Mean tumor-absorbed dose (A) and EUD (B) as function of patient response as assessed by Cheson et al. (19).